WO2012065950A1 - Silent fc variants of anti-cd40 antibodies - Google Patents
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- WO2012065950A1 WO2012065950A1 PCT/EP2011/070058 EP2011070058W WO2012065950A1 WO 2012065950 A1 WO2012065950 A1 WO 2012065950A1 EP 2011070058 W EP2011070058 W EP 2011070058W WO 2012065950 A1 WO2012065950 A1 WO 2012065950A1
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- C—CHEMISTRY; METALLURGY
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- 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
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- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- 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
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- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/565—Complementarity determining region [CDR]
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
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- 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
- C07K2317/71—Decreased effector function due to an Fc-modification
Definitions
- the present invention relates to silent constant fragment (Fc) variants of anti-CD40 antibodies and compositions and methods of use of said antibodies for treating pathological disorders such as autoimmune and inflammatory disorders and/or for preventing or reducing the risk of graft rejection in transplantation.
- Fc silent constant fragment
- CD40-CD154 interactions in intestinal inflammatory disorders such as Crohn's disease and ulcerative colitis
- mechanistic links of the CD40 pathway to pathology in more rare disorders such as autoimmune vasculitis, pemphigus vulgaris, and ITP also highlights the potential of anti-CD40 antibodies in these indications.
- the currently available immunosuppressants used after solid organ transplantation provide excellent short-tern efficacy. Acute rejections within the de novo period are observed in 5% - 20% of the recipients (depending on organ, patient population, and regimen) and the proportion of grafts lost to acute rejection within the de novo period is below 5% for any setting.
- CNI Calcineurin inhibitors
- Chir12.12 is a fully humanized, non-agonist anti-CD40 antibody (lgG1 , kappa) that blocks CD154 (also known as CD40 ligand; CD40L) -mediated leukocyte activation and can mediate antibody-dependent cellular cytotoxicity (ADCC) of human leukocytes and B cell lymphomas in vitro (see WO2006/073443).
- WO2005/044306 also describes anti-CD40 antagonist antibodies, including Chir12.12 for use in particular in the treatment of autoimmune and inflammatory disorders. Further Chir12.12 is effective in delaying kidney allograft rejection when dosed as a monotherapy in Macaca fascicularis (Cynomolgus monkeys) [Li et al.
- Anti-CD40 mAbs with silenced ADCC activity are predicted to have an improved safety profile relative to the parental anti-CD40 antibodies, and in particular may be more suitable for non-oncologic indications, such as autoimmune diseases and use in a transplant setting.
- the present invention therefore provides Fc silent anti-CD40 monoclonal antibodies that retain the non-agonistic, CD40L blocking attributes of the parental anti-CD40 antibody Chir12.12.
- the invention provides an isolated antibody or a protein comprising an antigen-binding portion of an antibody directed against the target CD40 polypeptide (SEQ ID NO:28), characterized in that said antibody or protein
- a) binds to CD40 polypeptide with a K D of 10nM or less, and,
- b) comprises a silent IgG Fc region.
- said antibody or protein inhibits CD40L induced signalling with an IC 50 of 50ng/ml or less.
- the isolated antibody or protein according to the invention has no or low agonist activity with respect to CD40 signalling.
- the antibody or protein according to the present invention comprises a silent IgG Fc region selected from the group consisting of the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18 or SEQ ID NO: 19.
- the isolated antibody or protein of the invention comprises heavy chain (V H ) and light chain (V L ) variable regions having at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent sequence identity to V H of Chir12.12 (SEQ ID NO:9) and V L of Chir12.12 antibody (SEQ ID NO: 10) respectively.
- antibodies according to the invention are mAb1 comprising heavy chain amino acid sequence of SEQ ID NO: 1 1 and light chain amino acid sequence of SEQ ID NO: 12, mAb2 comprising heavy chain amino acid sequence of SEQ ID NO: 13 and light chain amino acid sequence of SEQ ID NO: 14, or, - mAb3 comprising heavy chain amino acid sequence of SEQ ID NO: 15 and light chain amino acid sequence of SEQ ID NO: 16.
- the isolated antibody or protein according to the invention may be used as a medicament.
- they are suitable for use in the treatment of autoimmune disorders, inflammatory disorders and/or in preventing or reducing the risk of graft rejection in transplantation.
- the isolated antibody or protein according to the invention may be used in particular in the treatment of Multiple Sclerosis, Systemic Lupus Erythematosus, Sjogren's syndrome, Rheumatoid Arthritis, transplant rejection and graft-versus-host disease.
- the invention also relates to pharmaceutical compositions comprising the above antibodies or proteins according to the invention, in combination with at least a pharmaceutically acceptable excipient, diluent or carrier.
- Said pharmaceutical compositions may additionally comprise other active ingredients.
- the invention also relates to a lyophilisate or a liquid formulation of an antibody or protein according to the invention.
- the invention further relates to the isolated nucleic acid encoding the antibody or protein according to the invention and the corresponding cloning or expression vector comprising at least one nucleic acid selected from the group consisting of SEQ ID NOs: 22 to 27.
- the invention also relates to a host cell comprising one or more cloning or expression vectors as defined above.
- the invention further provides a process for the production of an antibody or a protein of the invention, comprising culturing the host cell as defined above, purifying and recovering said antibody or protein.
- immune response refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
- a “signal transduction pathway” or “signaling activity” refers to a biochemical causal relationship generally initiated by a protein-protein interaction such as binding of a growth factor to a receptor, resulting in transmission of a signal from one portion of a cell to another portion of a cell.
- the transmission involves specific phosphorylation of one or more tyrosine, serine, or threonine residues on one or more proteins in the series of reactions causing signal transduction.
- Penultimate processes typically include nuclear events, resulting in a change in gene expression.
- CD40 refers to human CD40, for example as defined in SEQ ID NO: 28, unless otherwise described.
- antibody as referred to herein includes whole antibodies and any antigen binding fragments (i.e., "antigen-binding portion") or single chains thereof.
- a naturally occurring "antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
- the light chain constant region is comprised of one domain, C L .
- V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- _ is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
- antigen-binding portion of an antibody refers to full length or one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a portion of CD40). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
- binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of the V
- a Fab fragment a monovalent fragment consisting of the V
- F(ab) 2 fragment a bivalent fragment comprising two Fab fragments linked by a disulf
- the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single chain protein in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883).
- single chain Fv single chain Fv
- Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
- IgG Fc region is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc region and variant Fc regions.
- the human IgG heavy chain Fc region is generally defined as comprising the amino acid residue from position C226 or from P230 to the carboxyl-terminus of the IgG antibody. The numbering of residues in the Fc region is that of the EU index of Kabat.
- the C- terminal lysine (residue K447) of the Fc region may be removed, for example, during production or purification of the antibody.
- a composition of antibodies of the invention may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
- An "isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to CD40 is substantially free of antibodies that specifically bind to other antigens than CD40).
- An isolated antibody that specifically binds to CD40 may, however, have cross- reactivity to other antigens, such as CD40 molecules from other (non-human) species.
- an isolated antibody may be substantially free of other cellular material and/or chemicals.
- monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
- a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- humanized antibody is intended to include antibodies that contain minimal sequence derived from non-human immunoglobulin sequences.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (also known as complementarity determining region or CDR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity.
- donor antibody such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity.
- complementarity determining region refers to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. See, e.g. Chothia et al.
- constant region refers to the portion of the antibody molecule that confers effector functions.
- mouse constant regions were substituted by human constant regions.
- the constant regions of the subject humanized antibodies were derived from human immunoglobulins. Humanization can be performed following the method of Winter and co- coworkers (Jones et al. (1986) Nature 321 :522-525; Riechmann et al.
- humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody.
- the humanized antibody of the invention will also comprise at least a portion of an immunoglobulin constant region (Fc). Typically, that of a human immunoglobulin and in the present case, a silent Fc IgG region.
- the antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
- humanized antibody include antibodies that comprise a silent variant of Fc IgG region.
- humanized monoclonal antibody refers to antibodies displaying a single binding specificity which have variable regions in which the variable regions are humunized from non-human sequences.
- recombinant antibody includes all human or humanized antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human or humanized antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences.
- Such recombinant human or humanized antibodies have variable regions in which the framework and CDR regions may be derived from human germline immunoglobulin sequences.
- such recombinant human or humanized antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V
- isotype refers to the antibody class (e.g., IgM, IgE, IgG such as lgG1 or lgG4) that is provided by the heavy chain constant region genes. Different isotypes have different effector function. For example, wild type human lgG1 and lgG3 isotypes mediate antibody-dependent cell-mediated cytotoxicity (ADCC) activity.
- ADCC antibody-dependent cell-mediated cytotoxicity
- an antibody recognizing an antigen and “an antibody specific for an antigen” and “an antibody directed against an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen”.
- an antibody or a protein that "specifically binds to CD40 polypeptide” is intended to refer to an antibody or protein that binds to human CD40 polypeptide with a K D of 100nM or less, 10nM or less, 1 nM or less.
- an antibody that "cross-reacts with an antigen other than CD40" is intended to refer to an antibody that binds that antigen with a K D of 1 ⁇ or less, 100nM or less, 10nM or less, 1 nM or less.
- An antibody that "does not cross-react with a particular antigen” is intended to refer to an antibody that binds to that antigen, with a K D of 100nM or greater, or a K D of 1 ⁇ or greater, or a K D of 10 ⁇ or greater.
- such antibodies that do not cross-react with the antigen exhibit essentially undetectable binding against these proteins in standard binding assays.
- K asS oc or "K a ", as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
- K dis or "K d ,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
- K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e. K d /K a ) and is expressed as a molar concentration (M).
- K D values for antibodies can be determined using methods well established in the art. A method for determining the K D of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore ® system.
- Affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with the antigen at numerous sites; the more interactions, the stronger the affinity.
- the term "Avidity” refers to an informative measure of the overall stability or strength of the antibody-antigen complex. It is controlled by three major factors: antibody epitope affinity; the valence of both the antigen and antibody; and the structural arrangement of the interacting parts. Ultimately these factors define the specificity of the antibody, that is, the likelihood that the particular antibody is binding to a precise antigen epitope.
- CD40 antagonist is intended to refer to an antibody or protein that inhibits CD40 induced signaling activity in the presence of CD40L in a human cell assay such as the CD40L-mediated PBMC proliferation assay. Such assay is described in more detail in the examples below.
- the antibodies or proteins of the invention inhibit CD40L induced signaling with an IC50 of 500ng/ml or less, preferably with an IC50 of 50ng/ml or less, for example with an IC50 of 20ng/ml or less, as measured in CD40L-mediated PBMC proliferation assay.
- an antibody with "no agonist activity” is intended to refer to an antibody that does not significantly increase CD40 mediated signaling activity in the absence of CD40L in a cell-based assay, such as the CD40L-mediated PBMC proliferation assay. Such assay is described in more details in the examples below.
- ADCC antibody-dependent cellular cytotoxicity activity refers to cell depleting activity. ADCC activity can be measured by the ADCC assay as described in more details in the Examples below.
- sient antibody refers to an antibody that exhibits no or low ADCC activity as measured in an ADCC assay as described in the Examples.
- the term "no or low ADCC activity” means that the silent antibody exhibits an ADCC activity that is below 50% specific cell lysis, for example below 10% specific cell lysis as measured in the ADCC assay as described in the Examples.
- No ADCC activity means that the silent antibody exhibits an ADCC activity (specific cell lysis) that is below 1 %.
- a silent antibody according to the invention does not exhibit any significant ADCC activity as measured in an ADCC assay as described in the Examples.
- Silenced effector functions can be obtained by mutation in the Fc region of the antibodies and have been described in the art: LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181 : 6664- 69; Strohl, W., supra).
- Examples of silent Fc lgG1 antibodies comprise the so-called LALA mutant comprising L234A and L235A mutation in the lgG1 Fc amino acid sequence.
- Another example of a silent lgG1 antibody comprises the D265A mutation.
- Another silent lgG1 antibody comprises the N297A mutation, which results in aglycosylated/non-glycosylated antibodies.
- the term “selectivity" for an antibody or protein of the invention refers to an antibody or protein that binds to a certain target polypeptide but not to closely related polypeptides.
- the term “high affinity” for an antibody refers to an antibody having a K D of 1 nM or less for a target antigen.
- the term “subject” includes any human or nonhuman animal.
- nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
- the term, "optimized" means that a nucleotide sequence has been altered to encode an amino acid sequence using codons that are preferred in the production cell or organism, generally a eukaryotic cell, for example, a cell of Pichia, a cell of Trichoderma, a Chinese Hamster Ovary cell (CHO) or a human cell.
- the optimized nucleotide sequence is engineered to retain completely or as much as possible the amino acid sequence originally encoded by the starting nucleotide sequence, which is also known as the "parental" sequence.
- the optimized sequences herein have been engineered to have codons that are preferred in CHO mammalian cells, however optimized expression of these sequences in other eukaryotic cells is also envisioned herein.
- the amino acid sequences encoded by optimized nucleotide sequences are also referred to as optimized.
- the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below.
- the percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4: 11-17, 1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
- the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol, Biol.
- Antibodies of the invention include the humanized recombinant antibodies mAb1-mAb3, isolated and structurally characterized by their full length heavy and light chain amino acid sequences as described in the Table 1 below: Table 1 : Full length heavy and light chain amino acid sequences of mAb1-mAb3
- variable regions, V H and V L amino acid sequences of such isolated antibodies mAb1-mAb3 of the invention all derived from the same antibody Chir12.12 previously described for example in WO2006/073443 and consisting of V H amino acid sequence of SEQ ID NO:7 and V L amino acid sequence of SEQ ID NO:8.
- One important difference of the antibodies of the invention compared to original CHIR12.12 is that they have an Fc region, consisting of a silent Fc IgG region, for example silent Fc lgG1 region.
- Table 2 summarizes the modification of Fc lgG1 region performed to obtain the antibodies mAb1-mAb3 as compared to original CHIR12.12 antibody.
- Table 2 Modification of Fc lgG1 region to obtain mAb1-mAb3
- antibodies of the invention include those having amino acids that have been mutated by amino acid deletion, insertion or substitution, yet have at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent identity with the V H and V L regions of CHIR12.12, respectively SEQ ID NO:7 and SEQ ID NO:8 and comprising a silent IgG Fc region, for example a silent lgG1 Fc region.
- the antibody of the invention is a mutant variant of any one of mAb1-mAb3, wherein said mutant variant antibody include mutant amino acid sequences wherein no more than 1 , 2, 3, 4 or 5 amino acids have been mutated by amino acid deletion, insertion or substitution in the V H and V L regions when compared with the V H and V L regions of CHIR12.12, respectively SEQ ID NO:7 and SEQ ID NO:8 and retaining the same constant regions as mAbl , mAb2 or mAb3.
- nucleic acids encoding antibodies of the invention include nucleic acids that have been mutated by nucleotide deletion, insertion or substitution, yet have at least 60, 70, 80, 90, 95, 96, 97, 98, 99 or 100 percent identity to the V H and V L corresponding coding regions of CHIR12.12, as depicted in the sequences described for example in SEQ ID NO:20 and SEQ ID NO:21 respectively and comprising a coding sequence of a silent IgG Fc region, for example, a silent lgG1 Fc region.
- it includes variant nucleic acids wherein no more than 1 , 2, 3, 4 or 5 nucleotides have been changed by nucleotide deletion, insertion or substitution in the V H and V
- mAb1-mAb3 In addition to the recombinant antibodies of the invention, mAb1-mAb3, the invention also encompasses homologous antibodies or proteins retaining the desired functional properties of mAb1-mAb3 antibodies.
- said homologous antibodies or proteins according to the invention are antibodies or proteins comprising an antigen-binding portion of an antibody directed against a target CD40 polypeptide (SEQ ID NO:28), characterized in that said antibody or protein
- a) binds to CD40 polypeptide with a K D of 10nM or less, and,
- b) comprises a silent IgG Fc region and wherein said homologous antibodies or proteins retain the desired functional properties of the original mAb1-mAb3 antibodies.
- Desired functional properties of the original mAb1-mAb3 antibodies may be selected from one ore more of the following properties:
- CD40 antagonist for example, it inhibits CD40L induced signaling as measured in CD40L-mediated PBMC proliferation assay
- said homologous antibodies or proteins according to the invention comprise a silent lgG1 Fc region, for example, a silent lgG1 Fc region selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 18 or SEQ ID NO: 19.
- the invention relates to an antibody or protein which has variable region heavy and light chain nucleotide sequences, or variable region heavy and light chain amino acid sequences, or all 6 CDRs amino acid sequences or nucleotide coding sequences that are homologous to the corresponding amino acid or nucleotide sequences of the antibodies mAb1-mAb3 described above, in particular in Table 1 , and said antibody or protein comprise a silent IgG Fc region selected from the group consisting of the Fc region of mAbl (SEQ ID NO: 17), the Fc region of mAb2 (SEQ ID NO: 18) and the Fc region of mAb3 (SEQ ID NO: 19), wherein said homologous antibody or protein specifically binds to CD40, and the antibody or protein exhibits the following functional properties: it is a CD40 antagonist, it exhibits no or low agonist activity, and it has no or low ADCC activity.
- the invention relates to antibodies or proteins homologous to mAb1-mAb3, comprising a silent IgG Fc region selected from the group consisting of the Fc region of mAbl (SEQ ID NO: 17), the Fc region of mAb2 (SEQ ID NO: 18) and the Fc region of mAb3 (SEQ ID NO: 19), and comprising a variable heavy chain (V H ) and a variable light chain (V L ) sequences where the CDR sequences share at least 60, 70, 90, 95, 96, 97, 98, 99 or 100 percent sequence identity to the corresponding CDR sequences of mAbl- mAb3, respectively SEQ ID NOs: 1-6, wherein said homologous antibody or protein specifically binds to CD40, and the homologous antibody or protein exhibits the following functional properties: it is a CD40 antagonist, it exhibits no or low agonist activity, and it has no or low ADCC activity.
- the homologous antibody or protein a) binds to CD40 with a K D of 1 nM or less; b) inhibits CD40L induced signaling with an IC50 of 50ng/ml or less as measured in CD40L-mediated PBMC proliferation assay described in the Examples; c) has no or low agonist activity as measured in a bioassay such as CD40L- mediated PBMC proliferation assay as described in the Examples; and, d) has no or low ADCC activity.
- the invention further relates to antibodies or proteins homologous to mAb1-mAb3, comprising a silent IgG Fc region selected from the group consisting of the Fc region of mAbl (SEQ ID NO: 17), the Fc region of mAb2 (SEQ ID NO: 18) and the Fc region of mAb3 (SEQ ID NO: 19), and comprising a variable heavy chain (V H ) and a variable light chain (V L ) sequences which share at least 80, 90, 95, 96, 97, 98, 99 or 100 percent sequence identity to the corresponding (V H ) and (V L ) sequences of mAb1-mAb3, respectively SEQ ID NO:7 and SEQ ID NO:8, wherein said homologous antibody or protein specifically binds to CD40, and the antibody or protein exhibits the following functional properties: it is a CD40 antagonist, it exhibits no or low agonist activity, and it has no or low ADCC activity.
- said homologous antibody or protein a) binds to CD40 with a K D of 1 nM or less; b) inhibits CD40L induced signaling with an IC50 of 50ng/ml or less as measured in CD40L-mediated PBMC proliferation assay described in the Examples; c) has no or low agonist activity as measured in a bioassay such as CD40L- mediated PBMC proliferation assay described in the Examples; and, d) has no or low ADCC activity.
- the invention relates to antibodies or proteins homologous to mAbl- mAb3 comprising a silent IgG Fc region selected from the group consisting of the Fc region of mAbl (SEQ ID NO: 17), the Fc region of mAb2 (SEQ ID NO: 18) and the Fc region of mAb3 (SEQ ID NO: 19), and wherein: the variable heavy and light chains are encoded by a nucleotide sequence that is at least 80%, at least 90%, at least 95%, or 100% identical to the corresponding coding nucleotide sequence of the variable heavy and light chains of mAb1-mAb3, wherein said homologous antibody or protein specifically binds to CD40, and the antibody or protein exhibits the following functional properties: it is a CD40 antagonist, it exhibits no or low agonist activity, and it has no or low ADCC activity.
- said homologous antibody or protein a) binds to CD40 with a K D of 1 nM or less; b) inhibits CD40L induced signaling with an IC50 of 50ng/ml or less as measured in CD40L-mediated PBMC proliferation assay described in the Examples; c) has no or low agonist activity as measured in a bioassay such as CD40L- mediated PBMC proliferation assay described in the Examples; and, d) has no or low ADCC activity.
- Antibodies with mutant amino acid sequences can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of the coding nucleic acid molecules, followed by testing of the encoded altered antibody for retained function (i. e., the functions set forth above) using the functional assays described in the Examples below.
- mutagenesis e.g., site-directed or PCR-mediated mutagenesis
- the antibodies or proteins homologous to mAb1-mAb3 as described above have conservative sequence modifications.
- amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, try
- Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
- Nucleic acid molecules encoding antibodies or proteins of the invention are known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
- Another aspect of the invention pertains to nucleic acid molecules that encode the antibodies or proteins of the invention as described above.
- Examples of light and heavy chains nucleotide sequences of any one of mAbl to mAb3 can be derived from the Table 3 (showing the entire nucleotide coding sequences of heavy and light chains of mAbl to mAb3).
- light and heavy chains nucleotide sequences according to the invention are any sequence coding for the full length heavy and/or light amino acid sequences of mAbl , mAb2 or mAb3 as described in Table 1.
- the invention also pertains to nucleic acid molecules that derive from the latter sequences having been optimized for protein expression in mammalian cells, for example, CHO cell lines.
- the nucleic acids may be present in whole cells, in a cell lysate, or may be nucleic acids in a partially purified or substantially pure form.
- a nucleic acid is "isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCI banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. 1987 Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York.
- a nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences.
- the nucleic acid is a cDNA molecule.
- the nucleic acid may be present in a vector such as a phage display vector, or in a recombinant plasmid vector.
- Nucleic acids of the invention can be obtained using standard molecular biology techniques. Once DNA fragments encoding, for example, V H and V L segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to an scFv gene.
- V L - or V H -encoding DNA fragment is operatively linked to another DNA molecule, or to a fragment encoding the antibody constant region of mAb1-mAb3 comprising Fc region as defined in SEQ ID NOs: 17-19.
- operatively linked is intended to mean that the two DNA fragments are joined in a functional manner, for example, such that the amino acid sequences encoded by the two DNA fragments remain in-frame, or such that the protein is expressed under control of a desired promoter.
- the isolated DNA encoding the V H region can be converted to a full-length heavy chain gene by operatively linking the V H -encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1 , CH2 and CH3).
- heavy chain constant regions CH1 , CH2 and CH3
- the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., el al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the heavy chain constant region may be selected among lgG1 isotypes comprising Fc region as defined in SEQ ID NOs: 17-19.
- the isolated DNA encoding the V L region can be converted to a full-length light chain gene (as well as to a Fab light chain gene) by operatively linking the V L -encoding DNA to another DNA molecule encoding the light chain constant region, CL.
- the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the light chain constant region can be a kappa or a lambda constant region.
- Antibodies or proteins of the invention can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229: 1202).
- DNAs encoding partial or full-length light and heavy chains can be obtained by standard molecular biology or biochemistry techniques (e.g., DNA chemical synthesis, PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
- operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
- the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
- the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
- the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
- the light and heavy chain variable regions of the antibodies described herein can be used to create full-length antibody genes by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired sequence corresponding to said constant regions of mAbl , mAb2 or mAb3 such that the V H segment is operatively linked to the C H segment(s) within the vector and the V L segment is operatively linked to the C L segment within the vector.
- the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
- the antibody chain gene can be cloned into the vector such that the signal peptide is linked in frame to the amino terminus of the antibody chain gene.
- the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
- the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
- the term "regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
- Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, CA 1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
- Regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus (e.g., the adenovirus major late promoter (AdMLP)), and polyoma.
- CMV cytomegalovirus
- SV40 Simian Virus 40
- AdMLP adenovirus major late promoter
- polyoma e.g., the adenovirus major late promoter (AdMLP)
- nonviral regulatory sequences may be used, such as the ubiquitin promoter or P-globin promoter.
- regulatory elements composed of sequences from different sources such as the SRa promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y.
- the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
- the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Patent Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.).
- the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
- Selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr- host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
- DHFR dihydrofolate reductase
- neo gene for G418 selection.
- the expression vector(s) encoding the heavy and light chains are transfected into a host cell by standard techniques.
- the various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
- the antibodies of the invention in either prokaryotic or eukaryotic host cells.
- Expression of antibodies in eukaryotic cells for example mammalian host cells, yeast or filamentous fungi, is discussed because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody.
- a cloning or expression vector according to the invention comprises either at least one of the following coding sequences (a)-(c), operatively linked to suitable promoter sequences:
- Mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described Urlaub and Chasin, 1980 Proc. Natl. Acad. Sci. USA 77:4216-4220 used with a DH FR selectable marker, e.g., as described in R.J. Kaufman and P.A. Sharp, 1982 Mol. Biol. 159:601- 621), CHOK1 dhfr+ cell lines, NSO myeloma cells, COS cells and SP2 cells.
- another expression system is the GS gene expression system shown in PCT Publications WO 87/04462, WO 89/01036 and EP 0 338 841.
- the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods (See for example Abhinav et al. 2007, Journal of Chromatography 848: 28-37).
- the host cell of the invention is a host cell transfected with an expression vector having the coding sequences selected from the group consisting of (a)- (c) suitable for the expression of mAb1-mAb3 respectively, operatively linked to suitable promoter sequences:
- the present invention features bispecific or multispecific molecules comprising an anti-CD40 antibody or protein of the invention.
- An antibody or protein of the invention can be derivatized or linked to another functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules.
- the antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multi-specific molecules that bind to more than two different binding sites and/or target molecules; such multi-specific molecules are also intended to be encompassed by the term "bispecific molecule" as used herein.
- an antibody or protein of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results.
- the present invention includes bispecific molecules comprising at least one first binding specificity for CD40, for example, one antigen-binding portion of any one of mAb1-mAb3 and a second binding specificity for a second target epitope.
- the second target epitope is another epitope of CD40 different from the first target epitope.
- Another example is a bispecific molecule comprising at least one first binding specificity for CD40, for example, one antigen-binding portion of any one of mAb1-mAb3 and a second binding specificity for an epitope within CD40.
- the molecule can further include a third binding specificity, in addition to the first and second target epitope.
- the bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, using methods known in the art. For example, each binding-specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation.
- cross-linking agents examples include protein A, carbodiimide, N-succinimidyl-S- acetyl-thioacetate (SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), o- phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-l-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al., 1984 J. Exp. Med.
- Conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, IL).
- the binding specificities are antibodies, they can be conjugated by sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains.
- the hinge region is modified to contain an odd number of sulfhydryl residues, for example one, prior to conjugation.
- both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell.
- This method is particularly useful where the bispecific molecule is a mAb x mAb, mAb x Fab, Fab x F(ab') 2 or ligand x Fab fusion protein.
- a bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Patent Number 5,260,203; U.S. Patent Number 5,455,030; U.S. Patent Number 4,881 ,175; U.S.
- Patent Number 5,132,405 U.S. Patent Number 5,091 ,513; U.S. Patent Number 5,476,786; U.S. Patent Number 5,013,653; U.S. Patent Number 5,258,498; and U.S. Patent Number 5,482,858.
- Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (REA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay.
- ELISA enzyme-linked immunosorbent assay
- REA radioimmunoassay
- FACS analysis bioassay (e.g., growth inhibition)
- bioassay e.g., growth inhibition
- Western Blot assay Western Blot assay.
- Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest.
- Multivalent antibodies e.g., an antibody
- the present invention provides multivalent antibodies comprising at least two identical or different antigen-binding portions of the antibodies of the invention binding to CD40, for example, selected from antigen-binding portions of any one of mAb1-mAb3.
- the multivalent antibodies provide at least two, three or four antigen-binding portions of the antibodies.
- the antigen-binding portions can be linked together via protein fusion or covalent or non covalent linkage. Alternatively, methods of linkage have been described for the bispecific molecules. Tetravalent compounds can be obtained for example by cross-linking antibodies of the antibodies of the invention with an antibody that binds to the constant regions of the antibodies of the invention, for example the Fc or hinge region.
- Methods of the invention are directed to the use of the anti-CD40 antibodies or proteins of the invention to treat subjects (i.e., patients) having an autoimmune disease and/or inflammatory disease, or a predisposition to developing an autoimmune disease and/or inflammatory disease, wherein the disease and/or inflammation is mediated by CD40L- mediated CD40 signaling on cells expressing the CD40 antigen.
- Methods for detecting CD40 expression in cells include, but are not limited to, PCR techniques, immunohistochemistry, flow cytometry, Western blot, ELISA, and the like.
- the methods of the invention are especially useful for treating inflammatory and/or autoimmune diseases wherein CD40L-mediated CD40 stimulation is involved.
- Inflammatory diseases are characterized by inflammation and tissue destruction, or a combination thereof.
- “Inflammatory disease” includes any inflammatory immune-mediated process where the initiating event or target of the immune response involves non-self antigen (s), including, for example, alloantigens, xenoantigens, viral antigens, bacterial antigens, unknown antigens, or allergens.
- inflammatory disease(s) includes “autoimmune disease(s)”.
- autoimmunity is generally understood to encompass inflammatory immune-mediated processes involving "self antigens. In autoimmune diseases, self antigen(s) trigger host immune responses.
- Transplant rejection or “graft rejection” refers to any host-mounted immune response against a graft including but not limited to HLA antigens, blood group antigens, and the like.
- the invention can also be used to treat graft versus host disease, such as that associated with bone marrow transplantation, for example.
- the donor bone marrow includes lymphocytes and cells that mature into lymphocytes.
- the donor's lymphocytes recognize the recipient's antigens as non-self and mount an inflammatory immune response.
- graft versus host disease or "graft versus host reaction” refers to any T cell mediated immune response in which donor lymphocytes react to the host's antigens.
- the antagonist anti-CD40 antibodies or proteins described herein can be used in accordance with the methods of the invention to treat autoimmune and/or inflammatory disorders including, but not limited to, systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, sarcoidosis, inflammatory arthritis, including juvenile arthritis, rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis, and gouty arthritis, rejection of an organ or tissue transplant, hyperacute, acute, or chronic rejection and/or graft versus host disease, multiple sclerosis, hyper IgE syndrome, polyarteritis nodosa, primary biliary cirrhosis, inflammatory bowel disease, Crohn's disease, celiac's disease (gluten-sensitive enteropathy), primary Sjogren's syndrome (pSS), autoimmune inflammatory disorders including, but not limited to, systemic lupus ery
- the anti-CD40 antibodies or proteins of the invention are useful in treating: (i) systemic lupus erythematosus (lupus nephritis), preferably in providing effective steroid-sparing therapies for induction and maintenance of remission, and prevention of end-stage renal disease; (ii) primary Sjogren's syndrome, preferably in prevention of salivary and lacrimary gland destruction, and induction and maintenance of remission of extraglandular manifestations; (iii) autoimmune thrombocytopenic purpura, preferably treatment of patients refractory to standard of care; (iv) ANCA-associated Vasculitides, preferably inducing and maintaining remission in patients refractory to corticosteroids, and steroid-sparing treatment; (v) Pemphigus Vulgaris, preferably in induction and maintenance of remission in patients refractory to corticosteroids, and steroid-sparing treatment; (vi) Multiple Sclerosis,
- the anti-CD40 antibodies or proteins of the invention are useful in treating pulmonary inflammation including but not limited to lung graft rejection, asthma, sarcoidosis, emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, chronic bronchitis, allergic rhinitis and allergic diseases of the lung such as hypersensitivity pneumonitis, eosinophilic pneumonia, bronchiolitis obliterans due to bone marrow and/or lung transplantation or other causes, graft atherosclerosis/graft phlebosclerosis, as well as pulmonary fibrosis resulting from collagen, vascular, and autoimmune diseases such as rheumatoid arthritis, scleroderma and lupus erythematosus.
- pulmonary inflammation including but not limited to lung graft rejection, asthma, sarcoidosis, emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, chronic
- Treatment is herein defined as the application or administration of an anti-CD40 antibody or protein according to the invention, for example, mAbl , mAb2 or mAb3 antibody, to a subject, or application or administration a pharmaceutical composition comprising said anti-CD40 antibody or protein of the invention to an isolated tissue or cell line from a subject, where the subject has an autoimmune disease and/or inflammatory disease, a symptom associated with an autoimmune disease and/or inflammatory disease, or a predisposition toward development of an autoimmune disease and/or inflammatory disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the autoimmune disease and/or inflammatory disease, any associated symptoms of the autoimmune disease and/or inflammatory disease, or the predisposition toward the development of the autoimmune disease and/or inflammatory disease.
- treatment is also intended the application or administration of a pharmaceutical composition comprising an anti-CD40 antibodies or protein of the invention, for example, mAbl , mAb2 or mAb3 antibody, to a subject, or application or administration of a pharmaceutical composition comprising said anti-CD40 antibody or protein of the invention to an isolated tissue or cell line from a subject, where the subject has an autoimmune disease and/or inflammatory disease, a symptom associated with an autoimmune disease and/or inflammatory disease, or a predisposition toward development of an autoimmune disease and/or inflammatory disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the autoimmune disease and/or inflammatory disease, any associated symptoms of the autoimmune disease and/or inflammatory disease, or the predisposition toward the development of the autoimmune disease and/or inflammatory disease.
- anti-inflammatory activity is intended a reduction or prevention of inflammation.
- Therapy with at least one anti-CD40 antibody or protein according to the invention causes a physiological response that is beneficial with respect to treatment of an autoimmune disease and/or inflammatory disease, where the disease involves cells expressing the CD40 antigen. It is recognized that the methods of the invention may be useful in preventing phenotypic change in cells such as proliferation, activation, and the like.
- At least one anti-CD40 antibody or protein of the invention as defined above herein is used to promote a positive therapeutic response with respect to treatment or prevention of an autoimmune disease and/or inflammatory disease.
- positive therapeutic response with respect to an autoimmune disease and/or inflammatory disease is intended an improvement in the disease in association with the anti-inflammatory activity of these antibodies or proteins, and/or an improvement in the symptoms associated with the disease. That is, an anti-proliferative effect, the prevention of further proliferation of the CD40-expressing cell, a reduction in the inflammatory response including but not limited to reduced secretion of inflammatory cytokines, adhesion molecules, proteases, immunoglobulins (in instances where the CD40 bearing cell is a B cell), combinations thereof, and the like, increased production of anti- inflammatory proteins, a reduction in the number of autoreactive cells, an increase in immune tolerance, inhibition of autoreactive cell survival, and/or a decrease in one or more symptoms mediated by stimulation of CD40-expressing cells can be observed.
- Such positive therapeutic responses are not limited to the route of administration and may comprise administration to the donor, the donor tissue (such as for example organ perfusion), the host, any combination thereof, and the like.
- Clinical response can be assessed using screening techniques such as magnetic resonance imaging (MRI) scan, x-radiographic imaging, computed tomographic (CT) scan, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistry, including but not limited to changes detectable by ELISA, RIA, chromatography, and the like.
- MRI magnetic resonance imaging
- CT computed tomographic
- FACS fluorescence-activated cell sorter
- terapéuticaally effective dose or amount or “effective amount” is intended an amount of anti-CD40 antibody or protein of the invention that, when administered brings about a positive therapeutic response with respect to treatment of a subject with an autoimmune disease and/or inflammatory disease.
- a therapeutically effective dose of the anti-CD40 antibody or protein of the invention for example, mAbl , mAb2 or mAb3 is in the range from 0. 01 mg/kg to 40 mg/kg, from 3 mg/kg to 20 mg/kg or from 7 mg/kg to 12 mg/kg. It is recognized that the method of treatment may comprise a single administration of a therapeutically effective dose or multiple administrations of a therapeutically effective dose of the antagonist anti-CD40 antibody or protein of the invention.
- a further embodiment of the invention is the use of anti-CD40 antibodies or proteins of the invention for diagnostic monitoring of protein levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials.
- suitable enzymes include horseradish peroxidase, alkaline phosphatase, P- galactosidase, or acetylcholinesterase
- suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin
- suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin
- an example of a luminescent material includes luminol
- examples of bioluminescent materials include luciferase, luciferin, and aequorin
- suitable radioactive material include l25 l, 131 l, 35 S, or 3 H.
- the anti-CD40 antibodies or proteins of the invention can be used in combination with any known therapies for autoimmune and inflammatory diseases, including any agent or combination of agents that are known to be useful, or which have been used or are currently in use, for treatment of autoimmune and inflammatory diseases.
- therapies and therapeutic agents include, but are not limited to, surgery or surgical procedures (e.g.
- splenectomy lymphadenectomy, thyroidectomy, plasmapheresis, leukophoresis, cell, tissue, or organ transplantation, intestinal procedures, organ perfusion, and the like
- radiation therapy such as steroid therapy and non-steroidal therapy
- hormone therapy for example, topical agents used to treat skin conditions such as allergies, contact dermatitis, and psoriasis
- immunosuppressive therapy for example, immunosuppressive therapy, and other antiinflammatory monoclonal antibody therapy, and the like.
- the antagonist anti-CD40 antibodies or proteins described herein are administered in combination with at least one other therapy, including, but not limited to, surgery, organ perfusion, radiation therapy, steroid therapy, non-steroidal therapy, antibiotic therapy, antifungal therapy, hormone therapy, cytokine therapy, therapy with dermatological agents (for example, topical agents used to treat skin conditions such as allergies, contact dermatitis, and psoriasis), immunosuppressive therapy, other anti- inflammatory monoclonal antibody therapy, combinations thereof, and the like.
- at least one other therapy including, but not limited to, surgery, organ perfusion, radiation therapy, steroid therapy, non-steroidal therapy, antibiotic therapy, antifungal therapy, hormone therapy, cytokine therapy, therapy with dermatological agents (for example, topical agents used to treat skin conditions such as allergies, contact dermatitis, and psoriasis), immunosuppressive therapy, other anti- inflammatory monoclonal antibody therapy, combinations thereof, and the like.
- the methods of the invention encompass co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order.
- these therapies can be given simultaneously, i.e., the anti-CD40 antibody or protein of the invention is administered concurrently or within the same time frame as the other therapy (i.e., the therapies are going on concurrently, but the anti-CD40 antibody or protein of the invention is not administered precisely at the same time as the other therapy).
- the anti-CD40 antibody of the present invention or protein of the invention may also be administered prior to or subsequent to the other therapy. Sequential administration of the different therapies may be performed regardless of whether the treated subject responds to the first course of therapy to decrease the possibility of remission or relapse.
- the anti-CD40 antibodies or proteins of the invention are administered in combination with immunosuppressive drugs or anti-inflammatory drugs, wherein the antibody or protein and the therapeutic agent (s) may be administered sequentially, in either order, or simultaneously (i.e., concurrently or within the same time frame).
- Suitable immunosuppressive drugs that can be administered in combination with the antagonistic anti-CD40 antibodies or proteins of the invention, for example mAbl , mAb2 or mAb3 antibody, include, but are not limited to, methotrexate, cyclophosphamide, mizoribine, chlorambucil, cyclosporine, such as, for example, aerosolized cyclosporine (see, U. S. Patent Application Publication No.
- tacrolimus FK506 ; ProGrafrM
- mycophenolate mofetil and azathioprine (6-mercaptopurine)
- sirolimus rapamycin
- deoxyspergualin leflunomide and its malononitriloamide analogs
- immunosuppressive proteins including, for example, anti-CTLA4 antibodies and Ig fusions, anti-B lymphocyte stimulator antibodies (e.g., LYMPHOSTAT-BTM) and Ig fusions (BLyS-lg), anti-CD80 antibodies and etanercept (Enbrel (RTM)), as well as anti-T cell antibodies such as anti-CD3 (OKT3), anti-CD4, and the like.
- Suitable anti- inflammatory agents include, but are not limited to, corticosteroids such as, for example, clobetasol, halobetasol, hydrocortisone, triamcinolone, betamethasone, fluocinole, fluocinonide, prednisone, prednisolone, methylprednisolone; non-steroidal anti- inflammatory drugs (NSAIDs) such as, for example, sulfasalazine, medications containing mesalamine (known as 5-ASA agents), celecoxib, diclofenac, etodolac, fenprofen, flurbiprofen, ibuprofen, ketoprofen, meclofamate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, rofecoxib, salicylates, sulindac, and tolmetin; phosphodiesterase-4 inhibitors, anti-inflammatory antibodies such as
- Transplant rejection and graft versus host disease can be hyperacute (humoral), acute (T cell mediated), or chronic (unknown etiology), or a combination thereof.
- the anti- CD40 antibodies or proteins of the invention for example mAbl , mAb2 or mAb3 antibody, are used in some embodiments to prevent and/or ameliorate rejection and/or symptoms associated with hyperacute, acute, and/or chronic transplant rejection of any tissue, including, but not limited to, liver, kidney, pancreas, pancreatic islet cells, small intestine, lung, heart, corneas, skin, blood vessels, bone, heterologous or autologous bone marrow, and the like.
- Graft tissues may be obtained from any donor and transplanted into any recipient host, and thus the transplant procedure may comprise transplanting animal tissue to humans (e.g. xenografts), transplanting tissue from one human to another human (e.g. allografts), and/or transplanting tissue from one part of a human's body to another (e.g. autografts).
- transplanting animal tissue to humans e.g. xenografts
- transplanting tissue from one human to another human e.g. allografts
- transplanting tissue from one part of a human's body to another e.g. autografts
- Treatment with the antibodies or proteins of the invention may also reduce transplantation sequelae such as fever, anorexia, hemodynamic abnormalities, leukopenia, white cell infiltration of the transplanted organ/tissue, as well as opportunistic infections.
- transplantation sequelae such as fever, anorexia, hemodynamic abnormalities, leukopenia, white cell infiltration of the transplanted organ/tissue, as well as opportunistic infections.
- the anti-CD40 antibodies or proteins of the invention may be used alone or in combination with immunosuppressive drugs to treat and/or prevent transplant rejection such as hyperacute, acute, and/or chronic rejection and/or graft versus host disease.
- the antibodies for example mAbl , mAb2 or mAb3 antibody, may be used in combination with suitable immunosuppressive drugs, including, but not limited, to methotrexate; cyclophosphamide; mizoribine; chlorambucil; cyclosporine, such as, for example, aerosolized cyclosporine (see, U. S.
- Patent Application Publication No.US20020006901 tacrolimus (FK506; ProGrafm), mycophenolate mofetil, and azathioprine (6-mercaptopurine), sirolimus (rapamycin), deoxyspergualin, leflunomide and its malononitriloamide analogs; immune modulators, including for example thalidomide and its analogs; and immunosuppressive proteins, including, for example, anti-CTLA antibodies and Ig fusions, anti-B lymphocyte stimulator antibodies (e.g., LYMPHOSTAT-BTM) and Ig fusions (BLyS-lg), anti-CD80 antibodies and etanercept (Enbrel (RTM)), as well as anti-T cell antibodies such as anti-CD3 (OKT3), anti-CD4, and the like.
- immunosuppressive proteins including, for example, anti-CTLA antibodies and Ig fusions, anti-B lymphocyte stimulator antibodies (e.g., LYMPHOSTAT-
- compositions and methods of the invention are used in combination with other drugs to further improve symptoms and outcomes in transplant recipients, such as those receiving lung or kidney grafts, for example.
- the anti-CD40 antibodies or proteins of the invention for example mAbl , mAb2 or mAb3 antibody, are used to treat transplant rejection (such as, for example hyperacute, acute, and/or chronic rejection or graft versus host disease in lung or renal transplant recipients) alone or in combination with parenterally and/or non-parenterally administered cyclosporine, including for example oral cyclosporine, injectable cyclosporine, aerosolized (e.g. inhaled) cyclosporine, and combinations thereof.
- transplant rejection such as, for example hyperacute, acute, and/or chronic rejection or graft versus host disease in lung or renal transplant recipients
- parenterally and/or non-parenterally administered cyclosporine including for example oral cyclosporine, injectable cyclosporine, aerosolized (e.g. inhaled
- the cyclosporine is delivered to the lung of the recipient by inhalation of cyclosporine in aerosol spray form using, for example, a pressurized delivery device or nebulizer.
- the cyclosporine may be administered in either dry powder or wet form.
- the cyclosporine may be administered as a sub therapeutic dose.
- the anti-CD40 antibodies or proteins of the invention may be used alone or in combination with immunosuppressive drugs to treat and/or prevent rheumatoid arthritis.
- the anti-CD40 antibodies or proteins of the invention are used to treat rheumatoid arthritis
- said antibodies or proteins may be used in combination with suitable immunosuppressive drugs, including, but not limited to, methotrexate, cyclophosphamide, mizoribine, chlorambucil, cyclosporine, tacrolimus (FK506; PROGRAFTM), mycophenolate mofetil, and azathioprine (6-mercaptopurine), sirolimus (rapamycin), deoxyspergualin, leflunomide and its malononitriloamide analogs; and immunosuppressive proteins, including, for example, anti-CTLA antibodies and Ig fusions, anti-B lymphocyte stimulator antibodies (e.g., LYMPHOSTAT-BTM) and Ig fusions (BLyS-lg), anti-CD20 antibodies (e.g.
- RITUXAN g
- HuMax-CD20 R-1594
- IMMU-106 TRU-015
- AME-133 tositumomab/1-131
- tositumomab Bexxar (D)
- ibritumomab tituxetan Zcvalin (RTM)
- anti-T cell antibodies such as anti-CD3 (OKT3), anti-CD4, and the like.
- treatment effectiveness may be assessed using any means and includes, but is not limited to, effectiveness as measured by clinical responses defined by the American College of Rheumatology criteria, the European League of Rheumatism criteria, or any other criteria. See for example, Felson et al. (1995) Arthritis. Rheum. 38 : 727-35 and van Gestel et al. (1996) Arthritis Rheum. 39: 34-40.
- the anti-CD40 antibodies or proteins of the invention may be used alone or in combination with immunosuppressive drugs to treat and/or prevent multiple sclerosis.
- the antibodies may be used in combination with suitable immunosuppressive drugs, including, but not limited to, methotrexate, cyclophosphamide, mizoribine, chlorambucil, cyclosporine, tacrolimus (FK506; PROGRAFTM), mycophenolate mofetil, and azathioprine (6-mercaptopurine), sirolimus (rapamycin), deoxyspergualin, leflunomide and its malononitriloamide analogs; and immunosuppressive proteins, including, for example, anti-CTLA antibodies and Ig fusions,
- the anti-CD40 antibodies or proteins of this invention are administered at a concentration that is therapeutically effective to prevent or treat autoimmune diseases and/or inflammatory diseases and/or to prevent or reduce risks associated to graft rejection in transplantation.
- the antibodies may be formulated using a variety of acceptable excipients known in the art.
- the antibodies or proteins are administered by injection, for example, either intravenously, intraperitoneally, or subcutaneously. Methods to accomplish this administration are known to those of ordinary skill in the art. It may also be possible to obtain compositions that may be topically or orally administered, or which may be capable of transmission across mucous membranes.
- Intravenous administration occurs preferably by infusion over a period of about 1 to about 10 hours, more preferably over about 1 to about 8 hours, even more preferably over about 2 to about 7 hours, still more preferably over about 4 to about 6 hours, depending upon the anti-CD40 antibody or protein being administered.
- the initial infusion with the pharmaceutical composition may be given over a period of about 4 to about 6 hours with subsequent infusions delivered more quickly.
- Subsequent infusions may be administered over a period of about 1 to about 6 hours, including, for example, about 1 to about 4 hours, about 1 to about 3 hours, or about 1 to about 2 hours.
- a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, (e.g., intravenous (IV), intramuscular (IM), intradermal, subcutaneous (SC), or infusion), oral and pulmonary (e.g., inhalation), nasal, transdermal (topical), transmucosal, and rectal administration.
- Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- the parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
- the anti-CD40 antibodies or proteins of the invention are typically provided by standard technique within a pharmaceutically acceptable buffer, for example, sterile saline, sterile buffered water, propylene glycol, combinations of the foregoing, etc.
- a pharmaceutically acceptable buffer for example, sterile saline, sterile buffered water, propylene glycol, combinations of the foregoing, etc.
- Methods for preparing parenterally administrable agents are described in Remington's Pharmaceutical Sciences (18th ed.; Mack Publishing Company, Eaton, Pennsylvania, 1990). See also, for example, WO 98/56418, which describes stabilized antibody pharmaceutical formulations suitable for use in the methods of the present invention.
- the amount of at least one antagonist anti-CD40 antibody or proteins of the invention to be administered is readily determined by one of ordinary skill in the art.
- Factors influencing the mode of administration and the respective amount of at least one antagonist anti-CD40 antibody or protein include, but are not limited to, the particular disease undergoing therapy, the severity of the disease, the history of the disease, and the age, height, weight, health, and physical condition of the individual undergoing therapy.
- the amount of antagonist anti-CD40 antibody or protein to be administered will be dependent upon the mode of administration and whether the subject will undergo a single dose or multiple doses of this agent. Generally, a higher dosage of anti-CD40 antibody or protein is preferred with increasing weight of the patient undergoing therapy.
- the dose of anti-CD40 antibody or protein to be administered is in the range from about 0.003 mg/kg to about 50 mg/kg, preferably in the range of 0.01 mg/kg to about 40 mg/kg.
- the dose can be 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 5 mg/kg, 7 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, or 50 mg/kg.
- the method comprises administration of multiple doses of antagonist anti-CD40 antibody or fragment thereof.
- the method may comprise administration of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a pharmaceutical composition comprising an antagonist anti-CD40 antibody or fragment thereof.
- the frequency and duration of administration of multiple doses of the pharmaceutical compositions comprising anti-CD40 antibody or protein can be readily determined by one of skill in the art.
- treatment of a subject with a therapeutically effective amount of an antibody or protein can include a single treatment or, preferably, can include a series of treatments.
- a subject is treated with antagonist anti-CD40 antibody or protein of the invention in the range of between about 0.1 to 20 mg/kg body weight, once per week for between about 1 to 10 weeks, preferably between about 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. Treatment may occur annually to prevent relapse or upon indication of relapse. It will also be appreciated that the effective dosage of antibody or antigen-binding fragment thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays as described herein.
- the dosing regimen includes a first administration of a therapeutically effective dose of at least one anti-CD40 antibody or protein of the invention on days 1 , 7, 14, and 21 of a treatment period.
- the dosing regimen includes a first administration of a therapeutically effective dose of at least one anti-CD40 antibody or protein of the invention on days 1 , 2, 3, 4, 5, 6, and 7 of a week in a treatment period.
- Treatment periods may be subsequent or separated from each other by a day, a week, 2 weeks, a month, 3 months, 6 months, or a year, ranges from 0.003 mg/kg to 50 mg/kg, from 0.01 mg/kg to 40 mg/kg, from 0.01 mg/kg to 30 mg/kg, from 0.1 mg/kg to 30 mg/kg, from 0.5 mg/kg to 30 mg/kg, from 1 mg/kg to 30 mg/kg, from 3 mg/kg to 30 mg/kg, from 3 mg/kg to 25 mg/kg, from 3 mg/kg to 20 mg/kg, from 5 mg/kg to 15 mg/kg, or from 7 mg/kg to 12 mg/kg.
- the dose of any one antagonist anti- CD40 antibody or antigen-binding fragment thereof for example the anti-CD40 monoclonal antibody or protein of the invention, can be 0.003 mg/kg, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 5 mg/kg, 7 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, or other such doses falling within the range of 0.003 mg/kg to 50 mg/kg.
- the same therapeutically effective dose of an anti- CD40 antibody or protein of the invention can be administered throughout each week of antibody dosing.
- an antagonist anti-CD40 antibody or protein of the invention can be used over the course of a treatment period.
- the initial therapeutically effective dose of an antagonist anti- CD40 antibody or antigen-binding fragment thereof as defined elsewhere herein can be in the lower dosing range (i.e., 0.003 mg/kg to 20 mg/kg) with subsequent doses falling within the higher dosing range (i.e., from 20 mg/kg to 50 mg/kg).
- the initial therapeutically effective dose of an antagonist anti- CD40 antibody or antigen-binding fragment thereof as defined elsewhere herein can be in the upper dosing range (i.e., 20 mg/kg to 50 mg/kg) with subsequent doses falling within the lower dosing range (i.e., 0.003 mg/kg to 20 mg/kg).
- the initial therapeutically effective dose of the antagonist anti-CD40 antibody or antigen- binding fragment thereof is 20 mg/kg to 35 mg/kg, including about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, and about 35 mg/kg
- subsequent therapeutically effective doses of the antagonist anti-CD40 antibody or protein of the invention are about 5 mg/kg to about 15 mg/kg, including about 5 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, and about 15 mg/kg.
- anti-CD40 therapy is initiated by administering a "loading dose" of the antibody or protein of the invention to the subject in need of anti- CD40 therapy.
- loading dose is intended an initial dose of the anti-CD40 antibody or protein of the invention that is administered to the subject, where the dose of the antibody or protein of the invention administered falls within the higher dosing range (i.e., from about 20 mg/kg to about 50 mg/kg).
- the "loading dose” can be administered as a single administration, for example, a single infusion where the antibody or antigen-binding fragment thereof is administered IV, or as multiple administrations, for example, multiple infusions where the antibody or antigen-binding fragment thereof is administered IV, so long as the complete "loading dose” is administered within about a 24-hour period.
- the subject is then administered one or more additional therapeutically effective doses of the anti-CD40 antibody or protein of the invention.
- Subsequent therapeutically effective doses can be administered, for example, according to a weekly dosing schedule, or once every two weeks, once every three weeks, or once every four weeks. In such embodiments, the subsequent therapeutically effective doses generally fall within the lower dosing range (i. e. 0.003 mg/kg to 20 mg/kg).
- the subsequent therapeutically effective doses of the anti-CD40 antibody or protein of the invention are administered according to a "maintenance schedule", wherein the therapeutically effective dose of the antibody or protein of the invention is administered once a month, once every 6 weeks, once every two months, once every 10 weeks, once every three months, once every 14 weeks, once every four months, once every 18 weeks, once every five months, once every 22 weeks, once every six months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or once every 12 months.
- the therapeutically effective doses of the anti-CD40 antibody or protein of the invention fall within the lower dosing range (i.e., 0.003 mg/kg to about 20 mg/kg), particularly when the subsequent doses are administered at more frequent intervals, for example, once every two weeks to once every month, or within the higher dosing range (i.e., from 20 mg/kg to 50 mg/kg), particularly when the subsequent doses are administered at less frequent intervals, for example, where subsequent doses are administered one month to 12 months apart.
- the lower dosing range i.e., 0.003 mg/kg to about 20 mg/kg
- the subsequent doses are administered at more frequent intervals, for example, once every two weeks to once every month
- the higher dosing range i.e., from 20 mg/kg to 50 mg/kg
- compositions comprising an anti-CD40 antibody or protein of the invention having the desired functional properties described herein as the therapeutically active component can be used in the methods of the invention.
- liquid, lyophilized, or spray-dried compositions comprising one or more of the anti-CD40 antibodies or proteins of the invention, for example, mAbl , mAb2 or mAb3 antibodies, may be prepared as an aqueous or non-aqueous solution or suspension for subsequent administration to a subject in accordance with the methods of the invention.
- Each of these compositions will comprise at least one of the anti-CD40 antibodies or proteins of the present invention as a therapeutically or prophylactically active component.
- the anti-CD40 antibody or protein of the invention is specifically incorporated into the composition to bring about a desired therapeutic or prophylactic response with regard to treatment, prevention, or diagnosis of a disease or condition within a subject when the pharmaceutical composition is administered to that subject.
- the pharmaceutical compositions comprise appropriate stabilizing agents, bulking agents, or both to minimize problems associated with loss of protein stability and biological activity during preparation and storage.
- Formulants may be added to pharmaceutical compositions comprising an anti-CD40 antibody or protein of the invention.
- These formulant may include, but are not limited to, oils, polymers, vitamins, carbohydrates, amine acids, salts, buffers, albumin, surfactants, or bulking agents.
- carbohydrates include sugar or sugar alcohols such as mono-, di-, or polysaccharides, or water soluble glucans.
- the saccharides or glucans can include fructose, glucose, mannose, sorbose, xylose, maltose, sucrose, dextran, pullulan, dextrin, a and ⁇ cyclodextrin, soluble starch, hydroxyethyl starch, and carboxymethylcellulose, or mixtures thereof.
- "Sugar alcohol” is defined as a C 4 to C 8 hydrocarbon having a hydroxyl group and includes galactitol, inositol, mannitol, xylitol, sorbitol, glycerol, and arabitol. These sugars or sugar alcohols may be used individually or in combination.
- the sugar or sugar alcohol concentration may be between 1.0% and 7% w/v, more preferably between 2.0% and 6.0% w/v.
- amino acids include levorotary (L) forms of carnitine, arginine, and betaine; however, other amino acids may be added.
- Preferred polymers include polyvinylpyrrolidone (PVP) with an average molecular weight between 2,000 and 3,000, or polyethylene glycol (PEG) with an average molecular weight between 3,000 and 5,000.
- PVP polyvinylpyrrolidone
- PEG polyethylene glycol
- Surfactants that can be added to the formulation are shown in EP Nos. 270,799 and 268,1 10.
- antibodies can be chemically modified by covalent conjugation to a polymer to increase their circulating half-life, for example.
- Preferred polymers, and methods to attach them to peptides are shown in U.S. Patent Nos. 4,766,106; 4, 179,337; 4,495,285; and 4,609,546.
- Preferred polymers are polyoxyethylated polyols and polyethylene glycol (PEG).
- PEG is soluble in water at room temperature and has the general formula: R (0 ⁇ CH2-CH2) n 0--R where R can be hydrogen, or a protective group such as an alkyl or alkanol group.
- the protective group has between 1 and 8 carbons, more preferably it is methyl.
- n is a positive integer, preferably between 1 and 1 ,000, more preferably between 2 and 500.
- the PEG has a preferred average molecular weight between 1 ,000 and 40,000, more preferably between 2,000 and 20,000, most preferably between 3,000 and 12,000.
- PEG has at least one hydroxy group, more preferably it is a terminal hydroxy group. It is this hydroxy group which is preferably activated to react with a free amino group on the inhibitor.
- the type and amount of the reactive groups may be varied to achieve a covalently conjugated PEG/antibody of the present invention.
- Water-soluble polyoxyethylated polyols are also useful in the present invention.
- POG polyoxyethylated sorbitol
- polyoxyethylated glucose polyoxyethylated glycerol
- POG polyoxyethylated glycerol
- the POG has a preferred molecular weight in the same range as PEG.
- the structure for POG is shown in Knauf et al. (1988, J. Bio. Chem. 263: 15064-15070) and a discussion of POG/IL-2 conjugates is found in U. S. Patent No. 4,766, 106.
- liposome Another drug delivery system for increasing circulatory half-life is the liposome.
- Methods of preparing liposome delivery systems are discussed in Gabizon et al. (1982) Cancer Research 42: 4734; Cafiso (1981) Biochem Biophys Acta 649: 129; and Szoka (1980) Ann. Rev. Bioplays. Eng. 9: 467.
- Other drug delivery systems are known in the art and are described in, e.g. , Poznansky et al. (1980) Drug Delivery Systems (R. L. Juliano, ed. , Oxford, N. Y. ) pp. 253-315; Poznansky (1984) Pharm Revs 36: 277.
- the formulant to be incorporated into a pharmaceutical composition should provide for the stability of the antagonist anti-CD40 antibody or protein of the invention. That is, the anti-CD40 antibody or protein of the invention should retain its physical and/or chemical stability and have the desired functional properties, i.e., one or more of the desired functional properties defined herein above.
- Methods for monitoring protein stability are well known in the art. See, for example, Jones (1993) Adv. Drug Delivery Rev. 10: 29-90; Lee, ed. (1991) Peptide and Protein Drug Delivery (Marcel Dekker, Inc., New York, New York); and the stability assays disclosed herein below. Generally, protein stability is measured at a chosen temperature for a specified period of time.
- a stable antibody pharmaceutical formulation provides for stability of the antagonist anti-CD40 antibody or protein of the invention when stored at room temperature (about 25°C) for at least 1 month, at least 3 months, or at least 6 months, and/or is stable at about 2-8 C for at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months.
- a protein such as an antibody when formulated in a pharmaceutical composition, is considered to retain its physical stability at a given point in time if it shows no visual signs (i.e., discoloration or loss of clarity) or measurable signs (for example, using size- exclusion chromatography (SEC) or UV light scattering) of precipitation, aggregation, and/or denaturation in that pharmaceutical composition.
- a protein such as an antibody when formulated in a pharmaceutical composition, is considered to retain its chemical stability at a given point in time if measurements of chemical stability are indicative that the protein (i.e., antibody) retains the biological activity of interest in that pharmaceutical composition.
- Methods for monitoring changes in chemical stability include, but are not limited to, methods to detect chemically altered forms of the protein such as result from clipping, using, for example, SDS-PAGE, SEC, and/or matrix-assisted laser desorption ionization/time of flight mass spectrometry; and degradation associated with changes in molecular charge (for example, associated with deamidation), using, for example, ion- exchange chromatography.
- An anti-CD40 antibody or protein of the invention when formulated in a pharmaceutical composition, is considered to retain a desired biological activity at a given point in time if the desired biological activity at that time is within about 30%, preferably within about 20% of the desired biological activity exhibited at the time the pharmaceutical composition was prepared as determined in a suitable assay for the desired biological activity.
- Assays for measuring the desired biological activity of the antagonist anti-CD40 antibodies or proteins disclosed herein can be performed as described in the Examples herein. See also the assays described in Schutze et al. (1998) Proc. Natl. Acad. Sci. USA 92: 8200-8204; Denton et al. (1998) Pediatr Transplant.
- the anti-CD40 antibody for example, selected among mAb1-mAb3 recombinant antibodies, is formulated in a liquid pharmaceutical formulation.
- the anti-CD40 antibody or protein of the invention can be prepared using any method known in the art, including those methods disclosed herein above.
- the anti-CD40 antibody for example, selected among the mAb1-mAb3 antibodies, is recombinantly produced in a CHO cell line.
- the anti-CD40 antibody can be formulated as a liquid pharmaceutical formulation in the manner set forth herein.
- the antagonist anti-CD40 antibody is to be stored prior to its formulation, it can be frozen, for example, at -20°C, and then thawed at room temperature for further formulation.
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, mAbl , mAb2 or mAb3 antibody.
- the amount of antibody present in the formulation takes into consideration the route of administration and desired dose volume.
- the liquid pharmaceutical composition comprises the anti-CD40 antibody, for example, mAbl , mAb2 or mAb3 antibody, at a concentration of 0.1 mg/ml to 300.0 mg/ml, 1.0 mg/ml to 200 mg/ml, 5.0 mg/ml to 100.0 mg/ml, 7.5 mg/ml to 50 mg/ml, or 15.0 mg/ml to 25.0 mg/ml.
- the liquid pharmaceutical composition comprises the anti-CD40 antibody, for example, mAbl , mAb2 or mAb3 antibody and a buffer that maintains the pH of the formulation in the range of pH 5.0 to pH 7.0.
- Suitable buffer that maintains the pH of the liquid anti-CD40 antibody formulation in the range of about pH 5.0 to about pH 7.0 can be used in the formulation, so long as the physicochemical stability and desired biological activity of the antibody are retained as noted herein above.
- Suitable buffers include, but are not limited to, conventional acids and salts thereof, where the counter ion can be, for example, sodium, potassium, ammonium, calcium, or magnesium.
- Examples of conventional acids and salts thereof that can be used to buffer the pharmaceutical liquid formulation include, but are not limited to, succinic acid or succinate, histidine or histidine hydrochloride, citric acid or citrate, acetic acid or acetate, tartaric acid or tartarate, phosphoric acid or phosphate, gluconic acid or gluconate, glutamic acid or glutamate, aspartic acid or aspartate, maleic acid or maleate, and malic acid or malate buffers.
- the buffer concentration within the formulation can be from 1 mM to 50 mM, including about 1 mM, 2 mM, 5 mM, 8 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, or other such values within the range of 1 mM to 50 mM.
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody, for example, the mAbl , mAb2 or mAb3 antibody, and succinate buffer or citrate buffer or histidine buffer or histidine hydrochloride buffer at a concentration that maintains the pH of the formulation in the range of about pH 5.0 to pH 7.0.
- succinate buffer or "citrate buffer” is intended a buffer comprising a salt of succinic acid or a salt of citric acid, respectively.
- histidine buffer is intended a buffer comprising a salt of the amino acid histidine.
- the buffer is a histidine buffer, e.g., histidine hydrochloride.
- the histidine buffer concentration within the formulation can be from 1 mM to 50 mM, including about 1 mM, 2 mM, 5 mM, 8 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, or other such values within the range of 1 mM to 50 mM.
- the succinate or citrate counterion is the sodium cation, and thus the buffer is sodium succinate or sodium citrate, respectively.
- any cation is expected to be effective.
- Other possible succinate or citrate cations include, but are not limited to, potassium, ammonium, calcium, and magnesium.
- the succinate or citrate buffer concentration within the formulation can be from 1 mM to 50 mM, including about 1 mM, 2 mM, 5 mM, 8 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, or other such values within the range of 1 mM to 50 mM.
- the liquid pharmaceutical formulation comprises the antagonist anti-CD40 antibody, for example, the mAbl , mAb2 or mAb3 antibody, at a concentration of 0.1 mg/ml to 300.0 mg/ml, or 1.0 mg/ml to 200 mg/ml, 5.0 mg/ml to 100.0 mg/ml, 7.5 mg/ml to 50 mg/ml, or 15.0 mg/ml to 25.0 mg/ml, and histidine or succinate or citrate buffer, for example, sodium succinate or sodium citrate buffer or histidine hydrochloride, at a concentration of 1 mM to 50 mM, 5 mM to 40 mM, 10mM to 35mM, preferably about 30 mM.
- the antagonist anti-CD40 antibody for example, the mAbl , mAb2 or mAb3 antibody
- histidine or succinate or citrate buffer for example, sodium succinate or sodium citrate buffer or histidine hydrochloride
- the liquid pharmaceutical formulation comprising a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody, and a buffer to maintain the pH of the formulation within the range of about pH 5.
- a buffer to maintain the pH of the formulation within the range of about pH 5.
- 0 to about pH 7.0 can further comprise an amount of an isotonizing agent sufficient to render the formulation near isotonic.
- the aqueous formulation has an osmolarity of 240 mmol/kg to 800 mmol/kg, preferably about 240 to about 600 mmol/kg, more preferably about 240 to about 440 mmol/kg, more preferably about 250 to about 330 mmol/kg, even more preferably about 260 to about 320 mmol/kg, still more preferably about 270 to about 310 mmol/kg.
- the isotonizing agent can be any reagent capable of adjusting the osmotic pressure of the liquid pharmaceutical formulation of the present invention to a value nearly equal to that of a body fluid. It is desirable to use a physiologically acceptable isotonizing agent.
- the liquid pharmaceutical formulation comprising a therapeutically effective amount of the antagonist anti-CD40 antibody, for example, the mAbl , mAb2 or mAb3 antibody and a buffer to maintain the pH of the formulation within the range of about pH 5.0 to about pH 7.0
- additional agents that are suitable for providing optimal tonicity of the liquid formulation.
- the liquid pharmaceutical formulation comprising a therapeutically effective amount of the anti-CD40 antibody, for example, the mAbl , mAb2 or mAb3 antibody, and a buffer to maintain the pH of the formulation within the range of about pH 5.0 to about pH 7.0, further comprises sodium chloride as the isotonizing agent.
- the concentration of sodium chloride in the formulation will depend upon the contribution of other components to tonicity. In some embodiments, the concentration of sodium chloride is 50 mM to 300 mM. In one such embodiment, the concentration of sodium chloride is about 150 mM.
- the concentration of sodium chloride is about 150 mM
- the buffer is sodium succinate or sodium citrate buffer at a concentration of 5 mM to 15 mM
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody
- the formulation has a pH of 5.0 to pH 7.0.
- the liquid pharmaceutical formulation comprises the anti-CD40 antibody or protein of the invention, for example, mAbl , mAb2 or mAb3 antibody, at a concentration of 0.1 mg/ml to 50.0 mg/ml or 5.0 mg/ml to 25.0 mg/ml, about 150 mM sodium chloride, and about 10 mM, 20mM 30 mM, 40 mM or 50mM sodium succinate or sodium citrate, at a pH of about pH 5.5.
- mAbl mAb2 or mAb3 antibody
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody, a buffer to maintain the pH of the formulation within the range of about pH 5.0 to about pH 7.0, and further comprises a surfactant.
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody, a buffer to maintain the pH of the formulation within the range of about pH 5.0 to about pH 7.0, an isotonizing agent such as sodium chloride at a concentration of about 50 mM to about 300 mM, and further comprises a surfactant.
- Typical surfactants employed are nonionic surfactants, including polyoxyethylene sorbitol esters such as polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20); polyoxypropylene-polyoxyethylene esters such as Pluronic F68; polyoxyethylene alcohols such as Brij 35; simethicone; polyethylene glycol such as PEG400; lysophosphatidylcholine; and polyoxyethylene-p-t-octylphenol such as Triton X-100.
- polyoxyethylene sorbitol esters such as polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20)
- polyoxypropylene-polyoxyethylene esters such as Pluronic F68
- polyoxyethylene alcohols such as Brij 35
- simethicone polyoxyethylene glycol
- lysophosphatidylcholine polyoxyethylene-p-t-octylphenol
- Triton X-100 Triton X-
- a preferred surfactant employed in the practice of the present invention is polysorbate 80. Where a surfactant is included, it is typically added in an amount from 0.001 % to 1.0% (w/v).
- the liquid pharmaceutical formulation comprises a therapeutically effective amount of the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody
- the buffer is sodium succinate or sodium citrate or histidine buffer or histidine hydrochloride buffer at a concentration of 1 mM to 50 mM, 3 mM to 40 mM, or 5 mM to 35 mM; or 7.5 mM to 30mM
- the formulation has a pH of pH 5.0 to pH 7.0
- the formulation further comprises a surfactant, for example, polysorbate 80, in an amount from 0.001 % to 1.0% or 0.001 % to 0.5%.
- Such formulations can optionally comprise an isotonizing agent, such as sodium chloride at a concentration of 50 mM to 300 mM, 50 mM to 200 mM, or 50 mM to 150 mM.
- the liquid pharmaceutical formulation comprises the anti-CD40 antibody or protein of the invention, for example, the mAbl , mAb2 or mAb3 antibody, at a concentration of 0.1 mg/ml to 200.0 mg/ml or 1 mg/ml to 100.0 mg/ml or 2 mg/ml to 50.0 mg/ml or 5.0 mg/ml to 25.0 mg/ml, including about 20.0 mg/ml; 50 mM to 200 mM sodium chloride, including about 150 mM sodium chloride; sodium succinate or sodium citrate at 5 mM to 20 mM, including about 10 mM sodium succinate or sodium citrate; sodium chloride at a concentration of 50 mM to 200 mM, including about 150 mM; histidine or histidine chloride at 5 mM to 50 mM, including about 30 mM histidine or histidine chloride; and optionally a surfactant, for example, polysorbate 80, in an amount from 0.001 % to 1.
- the liquid pharmaceutical formulation can be essentially free of any preservatives and other carriers, excipients, or stabilizers noted herein above.
- the formulation can include one or more preservatives, for example, antibacterial agents, pharmaceutically acceptable carriers, excipients, or stabilizers described herein above provided they do not adversely affect the physicochemical stability of the antagonist anti- CD40 antibody or antigen-binding fragment thereof.
- acceptable carriers, excipients, and stabilizers include, but are not limited to, additional buffering agents, co- solvents, surfactants, antioxidants including ascorbic acid and methionine, chelating agents such as EDTA, metal complexes (for example, Zn-protein complexes), and biodegradable polymers such as polyesters.
- liquid pharmaceutical formulation or other pharmaceutical composition described herein can be lyophilized to prevent degradation.
- Methods for lyophilizing liquid compositions are known to those of ordinary skill in the art.
- the composition may be reconstituted with a sterile diluent (Ringer's solution, distilled water, or sterile saline, for example) that may include additional ingredients.
- the composition is preferably administered to subjects using those methods that are known to those skilled in the art.
- the present invention also provides an antagonist anti-CD40 antibody or proteins of the invention for use in treating an autoimmune disease and/or inflammatory disease in a subject, wherein the medicament is coordinated with treatment with at least one other therapy.
- the medicament is to be used either prior to, during, or after treatment of the subject with at least one other therapy.
- other therapies include, but are not limited to, those described herein above, i.e. , surgery or surgical procedures (e.g.
- splenectomy lymphadenectomy, thyroidectomy, plasmapheresis, leukophoresis, cell, tissue, or organ transplantation, organ perfusion, intestinal procedures, and the like
- radiation therapy such as steroid therapy and nonsteroid therapy, hormone therapy, cytokine therapy, therapy with dermatological agents (for example, topical agents used to treat skin conditions such as allergies, contact dermatitis, and psoriasis), immunosuppressive therapy, and other anti-inflammatory monoclonal antibody therapy, and the like, where treatment with the additional therapy, or additional therapies, occurs prior to, during, or subsequent to treatment of the subject with the medicament comprising the antagonist anti-CD40 antibody or proteins of the invention as noted herein above.
- the present invention provides for mAbl , mAb2 or mAb3 antibody for use in the treatment of an autoimmune disease and/or inflammatory disease in a subject, wherein the medicament is coordinated with treatment with at least one other therapy as noted herein above.
- the medicament comprising the antagonist anti-CD40 antibody, for example, the monoclonal antibody mAbl , mAb2 or mAb3 disclosed herein, or antigen- binding fragment thereof is coordinated with treatment with two other therapies.
- medicament comprising the antagonist anti-CD40 antibody is coordinated with two other therapies
- use of the medicament can be prior to, during, or after treatment of the subject with either or both of the other therapies.
- the invention also provides for an antagonist anti-CD40 antibody, for example, the antibody mAbl , mAb2 or mAb3 disclosed herein, for use in treating an autoimmune disease and/or inflammatory disease in a subject, wherein the medicament is used in a subject that has been pretreated with at least one other therapy.
- an antagonist anti-CD40 antibody for example, the antibody mAbl , mAb2 or mAb3 disclosed herein, for use in treating an autoimmune disease and/or inflammatory disease in a subject, wherein the medicament is used in a subject that has been pretreated with at least one other therapy.
- pretreated or “pretreatment” is intended the subject has been treated with one or more other therapies prior to receiving the medicament comprising the antagonist anti- CD40 antibody or protein of the invention.
- FIGURE LEGENDS Figure 1 shows incorporation of 3 H-thymidine after 72 hours of human PBMC culture stimulated with a dose response of Chir12.12 (empty circle), mAbl (filled circle), mAb2 (filled square), mAb3 (filled triangle) or human CD40L (empty square).
- Figure 2 shows incorporation of 3 H-thymidine after 72 hours of human PBMC culture stimulated with a dose response of Chir12.12 (empty circle), mAbl (filled circle), mAb2 (filled square), mAb3 (filled triangle), human CD40L (empty square), isotype control (filled diamond) co-stimulated in the presence of either 5 ⁇ g/ml anti-lgM F(ab') 2 or 1 ⁇ CpG2006.
- Figure 3 shows incorporation of 3 H-thymidine after 72 hours of human PBMC culture stimulated with a dose response of Chir12.12 (empty circle), mAbl (filled circle), mAb2 (filled square), mAb3 (black triangle), human CD40L (empty square), isotype control (filled diamond) co-stimulated in the presence of 75ng/ml IL-4.
- Figure 4 shows incorporation of 3 H-thymidine after 72 hours of human PBMC culture stimulated with 20 ⁇ g/ml CD40L with a dose response of Chir12.12 (empty circle), mAbl (filled circle), mAb2 (filled square), mAb3 (black triangle) or human CD40L (empty square).
- Figure 5 shows dose-dependent binding of anti-human CD40 antibody to BJAB cell lines, respectively, Chir12.12 (filled circle), mAbl (empty square), mAb2 (empty triangle), mAb3 (filled triangle).
- Chir12.12 (1.9 mg/ml), mAbl (0.88 mg/ml), mAb2 (1.9 mg/ml), and mAb3 (1.9 mg/ml) were provided in 50 mM Citrate pH 7.0, 140 mM NaCI.
- An IgG isotype control was also used for select experiments (Sigma, St. Louis, USA).
- AfiniPure F(ab')2 fragment rabbit anti-human IgM was obtained from Jackson Immuno Research (Suffolk, UK), and CpG2006 was obtained from Microsynth (Balgach, Switzerland).
- Recombinant human CD40L was generated using standard procedures known to those of ordinary skill in the art.
- Supernatant containing human IL-4 was generated using standard procedures known to those of ordinary skill in the art.
- PBMC culture media RPMI-1640, 10 % FBS, 1 % Penicillin/Streptomycin, 1 % non essential amino acids, 1 % Sodium pyruvate, 5 mM ⁇ -mercaptoethanol (all from Invitrogen, San Diego, USA).
- PBMCs peripheral blood mononuclear cells
- PBMCs Primary PBMCs were purified from whole blood buffy coats obtained from healthy volunteers (Blutspendetechnik, Basel). Buffy coats were diluted 1 :4 with Ca2+ and Mg2+ free PBS containing 5 mM EDTA and 25 ml was aliquoted into 50 ml Falcon tubes. Diluted buffy coats were underlayed with 14 ml of Ficoll-Plaque Plus (GE Healthcare) per Falcon tube and centrifuged at room temperature for 20 min at 2250 rpm (no brake). Following centrifugation, the interphase layer was transferred to a single 50 ml Falcon tube. Interphase layers from multiple tubes (from a single donor) were combined up to a volume of 30 ml.
- Ficoll-Plaque Plus GE Healthcare
- PBS supplemented with 5 mM EDTA was added and cells were spun at room temperature for 5 min at 2250 rpm. The supernatant was discarded prior to addition of 15 ml red blood cell (RBC) lysis buffer and incubation at room temperature for 5 min. Subsequently 20 ml of PBS/5 mM EDTA was added and cells were spun again (RT/5 min at 2250 rpm). Cells were washed twice in PBS/5 mM EDTA (with intervening centrifugation steps) and re-suspended in 35 ml PBMC media prior to viable cell number determination using Trypan Blue dye exclusion. Cells not used immediately for in vitro stimulation were cryopreserved.
- RBC red blood cell
- PBMCs final density of 8x10 4 per well
- 3 H-thymidine (1 ⁇ /50 ⁇ / ⁇ ) was added to each well for the final 6 hours of culture prior to harvesting and determination of thymidine incorporation using a MicroBetaTrilux scintillation counter.
- Human PBMCs were stimulated as indicated in paragraph 1.2 above with a dose response of Chir12.12, mAbl , mAb2 or mAb3 for 3 days either in the absence of co- stimulation or in the presence of either 5 ⁇ g/ml anti-lgM F(ab')2 or 1 ⁇ CpG2006.. Proliferation was assessed by 3 H-thymidine incorporation after 72 hours of culture. Results are presented as the mean of triplicate cultures with SEM and are representative of 4 donors (independent experiments).
- Flow cytometry was used, in order to compare the binding of the different anti-CD40 antibody Fc variants in their binding to human BJAB cells. Therefore, 2 x 10 5 cells were seeded per well in a 96-well V-bottom plate. The plates were washed twice with 200 ⁇ _ of FACS buffer (PBS, 5 % FCS, 2 mM EDTA) for 2 min at 4°C at 1350 x g. Supernatants were discarded and cells were resuspended in 100 mL FACS buffer containing 8 % human serum (InVitromex, Cat. No. S4190) and incubated for 10 min.
- FACS buffer PBS, 5 % FCS, 2 mM EDTA
- Human PBMCs were prepared from human buffy coats provided by the Swiss Red Cross. The buffy coat was diluted 1 :5 in PBS (Invitrogen, Cat. No. 20012019) and distributed in 35 mL aliquots to 50 mL falcon tubes. Subsequently, 13 mL of Ficoll (GE Healthcare, Cat. No. 17 1440-02) were underlain in each tube. Cells were centrifuged at 1680 x g at RT for 20 min without break. The PBMC containing layer was collected and washed twice in a large volume of PBS for 5 min at 1000 x g. Finally cells were resuspended in 10 mL PBS and counted.
- PBS Human PBMCs were prepared from human buffy coats provided by the Swiss Red Cross. The buffy coat was diluted 1 :5 in PBS (Invitrogen, Cat. No. 20012019) and distributed in 35 mL aliquots to 50 mL falcon tubes. Subsequently
- Human monocytes were negatively isolated from the 100 x 10 7 PBMCs using the human monocyte isolation kit II from Miltenyi (Miltenyi, Germany, Cat. No. 130-091-153) on an AutoMACS instrument according to the manufacturer's instructions. After the isolation cells were washed twice for 5 min at 1000 x g at 4°C in culture medium (RPMI1640 (Invitrogen, Cat. No. 61870010), 10 % FCS (Invitrogen, Cat. No.16000044, US origin), 1 mM sodium pyruvate (Invitrogen, Cat. No. 11360039), 1 x NEAA (Invitrogen, Cat.No.
- DCs dendritic cells
- Immature DCs were harvested after 7 days of culture by rinsing the 6 well plates, pooling the cells and washing them twice for 5 min at 1400 x g in culture medium. Subsequently, 2 x 105 iDCs were seeded in 96-well flat-bottom plates (Becton Dickinson, Cat. No. 353072) in 100 ⁇ _. For the positive control cells were stimulated with MegaCD40L (Alexis, Cat. No. ALX-522-110-C010) at a concentration of 1 ⁇ g/mL, the negative control consisted of iDCs in medium only.
- MegaCD40L Alexis, Cat. No. ALX-522-110-C010
- anti-human CD40 antibody Fc variants were added at 10 ⁇ g/mL in a 1 :2 dilution together with 1 ⁇ g/mL MegaCD40L for a dose-response. Supernatants of the stimulated cells were collected 24 h later for the measurement of TNFa.
- agonism assay anti-human CD40 antibody Fc variants were added at 10 ⁇ g/mL in a 1 :2 dilution only and supernatants were collected after 48 h for the measurement of TNFa. Cells were seeded and stimulated in triplicates for all assays. 5.3 Measurement of TNF alpha by ELISA
- ELISA was performed as follows. Anti-TNFa capture antibody (BD Pharmingen, Cat. No. 551220) was coated on ELISA plates (Greiner, Nunc F96 Maxisorp, Cat. No. 442404) at 5 ⁇ g/mL in 50 ⁇ per well overnight at 4°C. For every washing step plates were washed 3 x with 250 ⁇ in a BioTek ELx 405 plate washer. After the first wash, 200 ⁇ _ of Superblock TBS (Thermo Scientific, Pierce, Cat. No. 37535) were incubated for 1 h at 37°C. Next, TNFa standard (recombinant human TNFa, R&D Systems, Cat. No.
- ELISA plates were washed and 50 ⁇ _ of the substrate p-Nitrophenylphosphat (Sigma, Cat. No. C-3041) was added to develop for 15 min.
- ELISA plates were read at 450nm with the software SoftMax Pro on a SpectraMax M5 (Molecular Devices).
- the primary initial purpose of the toxicology study was to investigate the potential toxicity of high dose (100 mg/kg) mAb1 in comparison to Chir12.12.
- mAb1 (50 mg/mL) was administered intravenously to one group of cynomolgus monkeys (5 males/5 females; group 2) at a dose level of 100 mg/kg and a dose volume of 2 mL/kg once weekly for 5 weeks (test item applications on days 1 , 8, 15, 22, 29, and 36).
- mAb1 placebo at a dose volume of 2 mL/kg was given to another group of cynomolgus monkeys which served as controls (5 males/5 females; group 1). All animals were subjected to necropsy one or two days after the last dosing. It was decided to incorporate Keyhole Limpet Hemocyanin (KLH)-immunization in order to evaluate the efficacy of both anti-CD40 Abs.
- KLH Keyhole Limpet Hemocyanin
- KLH specific IgM/lgG titers were determined with ELISA using cynomolgus monkey anti KLH IgM/lgG reference serum as standard. Blood was sampled on 3 pre-dose occasions and on day 15, 29 and at necropsy (day 37/38) for immunophenotyping of naive B cells (CD20+CD21+CD27-). Absolute naive CD20 B cell counts were calculated from the total lymphocyte count per blood sample and the relative naive CD20 B cell count by flow cytometry. Table 4: Summary of toxicology study
- T-cell dependent antibody response (TDAR) to KLH was examined to directly compare the influence of the fully ADCC-capable Chir12.12 with the mAbl .
- Blood was collected from all animals for toxicokinetic evaluation and for a possible anti-drug- antibody (ADA) evaluation.
- Human peripheral blood mononuclear cells were prepared as described previously in section 1.1.
- the tonsil capsule and connective tissue was removed and tonsil material after was cut the tonsil into ⁇ 5 mm big pieces prior to being mashed through a metal cell strainer with regular washing with B cell media. Tonsilar cells were then filtered twice through a 70 ⁇ cell strainer in order to remove cellular debris.
- B cells were isolated from fresh PBMCs using an EasySep Negative Selection Human B cell Enrichment Kit (Stemcell Technologies, Vancouver, BC, Canada). B cells were purified using an EasySep Negative Selection Human B cell Enrichment Kit as per manufacturer's instructions (Stemcell Technologies, Vancouver, BC, Canada).
- PBMCs rhesus, cynomolgus or human
- tonsil B cells human only
- purified labeled mAbl or isotype control antibodies in dose response (final concentration range 2.5 ⁇ g/ml - 0.00125 ⁇ g/ml).
- Cells were subsequently washed prior to being incubated with an anti-human (non-human primate cross-reactive) and a biotinylated anti-human IgG antibody with minimal cross- reactivity to NHPs (R10; note that it was possible to distinguish membrane IgG expressing human B cells either by including an anti-lgM stain or via differential intensity of FACS staining).
- mice where housed in single telemetry cages allowing visual contact with others.
- animals #5536/#5538 were housed together and the 4 remaining animals were kept isolated during the whole experiment (incompatible animals). All animals were housed under maintained temperature (20-24°C), at least 40% of humidity and natural light cycle. All were fed at least twice daily with mixture of fruits and vegetables. Water and Kliba Nafag 3446 pellets (Kaiseraugst, Germany) were provided ad libitum.
- Donor/recipient pairs were selected according to ABO match, DRB exon2 mismatch (Blancher A, Tisseyre P, Dutaur M, et al. (2006) Immunogenetics; 58(4):269-82) and responses in one-way Mixed lymphocyte reaction (MLR), having MLR-stimulation indices (MLR-SIs) >7 and ⁇ 47 (Bigaud M, Maurer C, Vedrine, et al. (2004) J. Pharmacol. Toxicol. Methods; 50(2):153-9). The results of this selection are shown in Table 6 and consisted in duo-transplant (swap transplant between 2 donors). Each recipient was implanted with a telemetric probe (Data Sciences Inc, USA) for monitoring arterial blood pressure, heart rate and motor activity.
- Donor kidneys were harvested, flushed with cold (4°C) University of Wisconsin solution (cold preservation time ⁇ 4 hours) and transplanted heterotopically, using standard microvascular techniques to create an end-to-side anastomosis between the graft renal vein and the recipient vena cava and between the graft renal artery and the recipient distal aorta (anastomosis time ⁇ 40 minutes).
- An uretero-cystoneostomy was performed upon appearance of urine from the graft. The native kidneys were removed.
- Post-operative analgesia was provided by buprenorphine, 0.01-0.02 mg/kg, i.m., three times daily); antibiotics (cefotaxime, 25 mg/kg, i.m., twice daily or ceftriaxon, 50 mg/kg, i.m. in 1 % lidocaine, four times daily).
- Analgesia and antibiotics were provided during 5 days. Whenever platelet counts experienced a marked increased or decreased, aspirin was administered at dose of 5 mg/kg i.m. daily (Aspegic, Sanofi-Aventis, Meyrin, Switzerland).
- Recipients were monitored for changes in clinical and cardiovascular conditions, body weight, food and water intake (supplemented to max. 100-150 ml/kg/day), urine output, hematology (using Beckmann Coulter ACT5Diff), serum and urine chemistry (using a Vetscan analyzer for daily SCrea/SUrea/SAmylase determination and a Beckmann Synchron CX5 analyzer for final confirmation of serum and urine samples). Serum creatinine (SCrea) and urea (SUrea) levels were used as markers of graft function. Transcutaneous ultrasound-guided biopsies were performed with a 16G needle, as described previously (Gaschen L, Kunkler A, Menninger K, et al. (2001) Vet. Radiol.
- Recipients were ultimately euthanized in case of (i) severe graft failure (e.g. Screa >500 ⁇ / ⁇ or Surea >20mmol/l) associated or not with increased ultrasound score; or (ii) general health problems and/or overt clinical signs of distress. At necropsy, the kidney allografts were collected (including ureter and anastomosis), together with all other major organs, and processed for subsequent histological analysis. Table 6: General information about the donor/recipient combinations and treatment regimens used
- mAb1 was provided in liquid form being freshly thawed on the day of infusion from -80°C. The application of 30 mg/kg/i.v. was done once weekly, excepting for the first three doses on day -1 , 0 and 1 (pre- and post-transplant).
- CsA for oral administration (p.o.) was a microemulsion preconcentrate (Sandimmun Neoral (RTM) drink solution, 100 mg/ml, Novartis Pharma AG). CsA was applied at a daily dose (starting on day -1) of 20 mg/kg/p.o., in combination with mAbl (see Table 6). 8.2.3 Monitoring of mAbl Pharmacokinetics (PK), immunogenicity (primate anti- human antibody) and pharmacodynamics (PD)
- Blood samples 500 ⁇ serum were collected (prior to i.v. dosing) for the determination of mAbl exposures at day -1 , 3, 7 (baseline and 15 min), 14, 28, 42, 56, 70, 84 and 100.
- CsA determinations blood samples were collected before oral dosing or CsA (C0/C24) and 2 hours after the application (C2).
- C2 corresponds to the peak levels of CsA absorption. All the material was stored at -80°C until further processing (CsA detection kit, Hot Star Taq Master Mix, Qiagen Minnesota, US).
- Samples for mAbl- immunogenicity were collected (50 ⁇ serum) on days -1 , 7, 14, 28, 42, 56, 70, 84 and 100 in kept frozen -80°C. Briefly, ninety-six well microtiter plates were coated with recombinant human CD40. These were stored at 4°C nominal overnight. Following blocking, Calibrator standards (Cs), Quality Control (QC) samples and sample specimens containing mAbl were added to the plate. The plate was incubated at +25°C nominal for 120 minutes with agitation. Following washing of the plate, mouse anti human kappa light chain antibody followed by HRP goat anti mouse (H+L) conjugate was added to the plate to detect any mAbl bound to the recombinant CD40.
- Cs Calibrator standards
- QC Quality Control
- CD20+ and CD3+ cells were counted with TruCount Tubes (Becton Dickinson, cat# 340334) used according to the manufacturer's instructions with an anti-human CD40-APC mAb (Clone 5C3, Becton Dickinson, cat# 555591), an anti-human CD3-PerCP (Clone SP34-2, Becton Dickinson, cat# 552851) and of anti-human CD20-FITC mAb (Clone LT20, Immunotools, cat# 21279203X2). Data was acquired on an LSRII flow cytometer (Becton Dickinson Biosciences) using DIVA (version 6.1.1) software. Lymphocytes and beads were gated in the FSC/SSC dot blot according to size and granularity and further analyzed for expression of CD20 and CD3.
- an anti-human CD40-APC mAb Clone 5C3, Becton Dickinson, cat# 555591
- C4b is considered a stable and reliable marker of acute humoral rejection (AHR).
- AHR acute humoral rejection
- the second slide serves as negative control by applying rabbit isotype control (Zymed Laboratories Inc, USA) instead of primary antibody;
- Example 1 Evaluation of the agonistic activity of mAb1 , mAb2 and mAb3
- the experimental data are based on the use of isolated, unfractionated primary human PBMCs.
- Whole PBMC preparations (instead of isolated B cells or monocytes) more closely mimics the in vivo situation where an anti-CD40 mAb could have multiple direct and indirect effects on different leukocyte cell types.
- PBMC proliferation assay it was determined that aglycosylated anti-CD40 mAbs mAbl (N297A) and mAb2 (D265A), which retained the amino acid sequence of the antigen binding portion unchanged from the parental Chir12.12 antibody, retained the non agonistic, CD40L blocking properties of the parental Chir12.12 mAb.
- the antibody mAb3 (LALA mutant) was weakly agonistic in the presence of IL-4.
- PBMCs proliferated in response to CD40L.
- mAbl or mAb2 could enhance CpG2006 or anti-lgM F(ab') 2 induced proliferation of PBMCs ( Figure 2).
- Chir12.12 failed to enhance anti- lgM F(ab') 2 induced proliferation of PBMCs, however unlike mAbl and mAb2 it completely inhibited CpG induced PBMC proliferation.
- CpG2006 is a synthetic ligand for Tolllike receptor 9 (TLR9), a receptor demonstrated to bind pathogen and host derived ssDNA.
- TLR9 Tolllike receptor 9
- B cells B cells and (to a lesser extent) monocytes in peripheral blood.
- CpG containing ODNs have previously been shown to enhance ADCC (Moga, et al. 2008), it can be speculated that CpG2006 is able to enhance ADCC mediated by the germline lgG1 Fc portion of the parental Chir12.12 mAb.
- Example 2 Evaluation of the ability of the Fc silent anti-CD40 mAbs to block CD40L-mediated PBMC proliferation
- binding of the three variants mAbl , mAb2 and mAb3 was tested in comparison to the parental Chir12.12 on a B cell line, BJAB, which constitutively expresses CD40. Binding was tested in a dose-titration starting at 10 ⁇ g/mL in a 1 :2 dilution.
- Example 4 Stimulation/Inhibition of TNF alpha release from human monocytes derived dendritic cells by the anti-CD40 Fc variants
- the parental Chir12.12 antibody blocks the interaction of CD40-CD40L and therefore should also block cell activation. Stimulation of CD40 on human monocyte-derived dendritic cells with CD40L trimers leads for example to the release of pro-inflammatory cytokines like TNFa (Ma 2009). Again, the change in the Fc region should not impact the blocking function of the variants in comparison to Chir12.12. All four antibodies should inhibit CD40L- mediated TNFa release from human MoDCs with an equivalent IC50. Therefore, seven day old human MoDCs were stimulated for 24 h with MegaCD40L, a double trimeric, recombinant construct in the presence of all four blocking anti-CD40 variants.
- the primary objective of the toxicology study was to determine the toxicity of mAbl , following once weekly intravenous administration to the cynomolgus monkey for 5 weeks (6 test item applications).
- the non-silent (ADCC) version of this antibody (Chir12.12) was also used in order to compare the effects of an ADCC-active antibody with the ADCC- silent version (mAbl).
- Blood coagulation was not affected by treatment with mAbl or Chir12.12 as assessed by prothrombin time, activated partial prothrombin time, and fibrinogen. Platelet counts appeared in the normal range. P-selectin or sCD40L concentrations in plasma did not indicate platelet activation.
- T-cell dependent antibody reaction showed that, in comparison to the control group, no IgG and IgM response to KLH was observed in the mAbl- or Chir12.12-treated animals.
- TDAR T-cell dependent antibody reaction
- Toxicokinetic evaluation revealed that trough concentrations increased during the course of the study indicating accumulation of mAbl and Chir12.12.
- Mean trough concentrations after the 4 th and 5 th dose were similar, indicating close-to-steady state conditions after the 5 dose for mAb1 and Chir12.12.
- Mean exposures (both genders) over the dosing interval (AUC T ) after the 4 th and 5 th dose were 906 and 990 h.mg/mL, respectively for mAb1 , and 757 and 751 h.mg/mL, respectively for Chir12.12.
- the AUC T values were also indicative of close-to-steady state conditions after the 5 th dose.
- Macroscopic examinations did not show any evidence of target organ toxicity, and organ weights were also within the normal range for this species.
- the effects on B-cells are the desired pharmacologic actions and therefore not considered to be adverse.
- the no-observable-adverse-effect level (NOAEL) is considered to be at the dose of 100 mg/kg for both mAbl and Chir12.12 under the conditions of this study.
- the binding and functional cross-reactivity of mAbl was determined between human, Rhesus and Cynomolgus leukocytes. Table 10 shows a direct comparison of the binding EC50s for mAbl in all three species. Table 10: Human and NHP cross-reactivity of mAbl .
- mAbl binds to CD20+ cells (B cells) of all three species with comparable EC50. Additionally, mAbl could inhibit CD154+IL-4 induced proliferation of human tonsil B cells as well as PBMCs from Cynomolgus and Rhesus. Collectively these results indicated that the ability of mAbl to bind CD40 and inhibit CD154-induced proliferation of human B cells or non-human primate PBMCs was very similar. The availability of in vitro receptor occupancy (RO) data and functional inhibition enabled the relationship between these two variables to be determined for each species (Table 11).
- RO in vitro receptor occupancy
- Tonsil B cells assuming in vivo KD in rhesus and in human is the same as the one computed in the PK/PD study in cyno. c assuming mAbl is well above [target] the Hill-Langmuir equation is applicable. The results indicate that approximately 2-fold less RO is required by mAbl Rhesus PBMCs to inhibit PBMC proliferation by 50% in comparison to human B cells. In human, full inhibition could be obtained with ca. 75% (in vivo predicted) RO.
- Combination treatment with mAbl (30 mg/kg i.v.) and Cyclosporine A, 20 mg/kg orally during allograft kidney transplantation resulted in a significant prolongation of the survival of the 6 animals involved in the study.
- the grafts were functional during >91*, 31 , >92*, >92*, >98* and >98* days (mean: >83.6 days) in animals #5529, #5533, #5523, #5524, #5536 and #5538, respectively (* end of protocol).
- the survival in untreated animals (or treated with sub-therapeutic IS-doses) ranged from 7-10 days (historical data).
- Animal #5533 was euthanized 31 days post-transplant, due to acute kidney failure and anuria. This pathology appeared after maintained hypertensive period and anaesthesia for biopsy collection. Monitoring post-transplant
- SCrea was the main parameter used for the evaluation of the kidney function. In all 6 animals, SCrea levels increased above the baseline levels one day after transplant (from 81.8 ⁇ 14.6 to 221.5 ⁇ 37.1 ⁇ / ⁇ ). Such rise in SCrea is a common feature during the first week post-transplant (Table 12).
- Table 12 Changes in SCrea observed in NHP kidney allograft recipients treated with mAbl and CsA combination therapy at 30 and 20 mg/kg, respectively
- Table 13 Changes in SUrea observed in NHP kidney allograft recipients treated with mAb1 and CsA combination therapy at 30 and 20 mg/kg, respectively
- Table 14 Serum amylase concentrations (U/L) in kidney transplanted animals treated with a combination of mAbl at 30 mg/kg i.v. and CsA at 20 mg/kg p.o.
- a rapid and marked body weight loss could be mainly observed in animals #5529, #5533 and #5536. In all six transplanted animals, it ranged from -4 to -18% during the first 21 days following transplant. However, body weight loss tended to recover after that time point and towards the end of the study.
- Platelet counts were normal (300-400 cells x 103/ ⁇ ) or increased during the post- transplant period 600-800 cells x 103/ ⁇ .
- Animal #5529 received aspirin treatment during 3 days (day 7-9) due to quick increase in platelet counts.
- Animal #5533 presented long term thrombocytosis (>1000 cells x 103/ ⁇ ) and received aspirin treatment between days 7-26.
- Transplant study - discussion The goal of the transplant study was to assess, in a non-human primate model of kidney allograft rejection, the beneficial effects of mAbl when given as combination therapy with sub-therapeutic dose of Cyclosporine A. In addition, it was of relevance to assess the absence of side effects in a model where systemic inflammation is induced.
- mAbl When applied as combination therapy with a subtherapeutic dose of CsA (20mg/kg p.o.), mAbl demonstrated efficacy in increasing the survival of kidney allografts in NHPs. The mean graft survival was >83.6 days and 5 out of 6 animals reached the end of the experimental protocol (established in 91-98 days).
- mAbl non-agonist blocking anti-CD40 antibody
- kidney function was euthanized on day 31 due to acute kidney failure (no rejection). This outcome was caused by an incomplete recovery of the kidney function after the transplantation procedure.
- the signs indicating poor kidney function were high SUrea levels (1 1-19 mmol/l) or maintained high SCa concentrations (>2.8 mmol/l).
- the terminal graft loss was accelerated by a maintained hypertension (>140 mmHg systolic) combined with hypotension observed during anesthesia applied during the biopsy collection procedure and high hypertensive peaks registered the night before euthanasia (-170 mmHg systolic) (Palmer BF (2002) N. Engl. J. Med; 347(16): 1256-1261). All those events could not be attributed to mAbl treatment and only to individual differences in the post- transplant phase.
- a partial depletion could be observed with time in all treated animals. This partial depletion is probably not due to active Fc-receptor mediated depletion as mAbl is a silenced antibody, which does not bind FcR nor mediates in vitro ADCC.
- the partial depletion can be a mirror of the lack of germinal centers, which is observed in the histology at the end of the experiment. This partial depletion may be due to the lack of survival signals.
- the results of the transplant study support the use of mAbl (and by extension, the other antibodies and proteins of the invention) as valid targets for the treatment of kidney rejection in a combination therapy with an excellent safety profile.
- the excellent safety profile and efficacy further support the use of the antibodies of the invention in the treatment of autoimmune disorders and/or inflammatory disorders, and prevention of transplant rejection mediated by CD40L-mediated CD40 signaling on cells expressing the CD40 antigen.
- Anti-CD40 antibodies have not been reported to induce hemostatic events in patients, however elevations in pancreatic enzymes in B cell lymphoma patients receiving the anti- CD40 Ab Chir12.12 and the possible risk of pancreatitis precludes the use of this Fc- competent anti-CD40 antibody in chronic autoimmune disease and transplantation for safety reasons.
- mAbl was able to prolong non-human primate renal allograft survival in combination with sub-therapeutic doses of cyclosporine.
- mAbl was able to completely suppress primary and secondary antibody responses to immunization with a T cell-dependent antigen.
- mAbl would be a safe and efficacious therapeutic, and could be used to treat patients suffering from B lymphocyte and antigen presenting cell driven autoimmune disease or undergoing allograft transplant where CD40-CD154 interactions are involved in contributing to pathology.
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CN201180054907.0A CN103209996B (en) | 2010-11-15 | 2011-11-14 | The reticent Fc variant of anti-CD 40 antibodies |
SI201131224A SI2640749T1 (en) | 2010-11-15 | 2011-11-14 | Silent fc variants of anti-cd40 antibodies |
EP11781571.2A EP2640749B1 (en) | 2010-11-15 | 2011-11-14 | Silent fc variants of anti-cd40 antibodies |
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Citations (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4495285A (en) | 1981-10-30 | 1985-01-22 | Kimihiro Shimizu | Plasminogen activator derivatives |
US4609546A (en) | 1982-06-24 | 1986-09-02 | Japan Chemical Research Co., Ltd. | Long-acting composition |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
WO1987004462A1 (en) | 1986-01-23 | 1987-07-30 | Celltech Limited | Recombinant dna sequences, vectors containing them and method for the use thereof |
EP0268110A1 (en) | 1986-10-27 | 1988-05-25 | Cetus Oncology Corporation | Pharmaceutical compositions of recombinant interleukin-2 and formulation processes |
EP0270799A1 (en) | 1986-10-27 | 1988-06-15 | Cetus Oncology Corporation | Pharmaceutical compositions of recombinant beta-interferon and formulation processes |
US4766106A (en) | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
WO1989001036A1 (en) | 1987-07-23 | 1989-02-09 | Celltech Limited | Recombinant dna expression vectors |
EP0338841A1 (en) | 1988-04-18 | 1989-10-25 | Celltech Limited | Recombinant DNA methods, vectors and host cells |
US4881175A (en) | 1986-09-02 | 1989-11-14 | Genex Corporation | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
US5013653A (en) | 1987-03-20 | 1991-05-07 | Creative Biomolecules, Inc. | Product and process for introduction of a hinge region into a fusion protein to facilitate cleavage |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5132405A (en) | 1987-05-21 | 1992-07-21 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
US5476786A (en) | 1987-05-21 | 1995-12-19 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5674492A (en) | 1993-12-23 | 1997-10-07 | Immunex Corporation | Method of preventing or treating disease characterized by neoplastic cells expressing CD40 |
US5847082A (en) | 1994-03-03 | 1998-12-08 | Alexion Pharmaceuticals, Inc. | Terminal complement inhibitor fusion proteins |
WO1998056418A1 (en) | 1997-06-13 | 1998-12-17 | Genentech, Inc. | Stabilized antibody formulation |
US20020006901A1 (en) | 1999-02-05 | 2002-01-17 | Aldo T. Iacono | Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease |
US20020119151A1 (en) | 1997-06-20 | 2002-08-29 | Biogen, Inc. | CD154 blockade therapy for therapeutic protein inhibitor syndrome |
WO2005044306A2 (en) | 2003-11-04 | 2005-05-19 | Chiron Corporation | Use of antagonist anti-cd40 antibodies for treatment of autoimmune and inflammatory diseases and organ transplant rejection |
WO2006073443A2 (en) | 2004-04-27 | 2006-07-13 | Novartis Vaccines And Diagnostics, Inc. | Antagonist anti-cd40 monoclonal antibodies and methods for their use |
WO2008150494A1 (en) * | 2007-05-30 | 2008-12-11 | Xencor, Inc. | Methods and compositions for inhibiting cd32b expressing cells |
CA2759146A1 (en) * | 2009-04-20 | 2010-10-28 | Kyowa Hakko Kirin Co., Ltd. | Agonist anti-cd40 antibody |
Family Cites Families (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4766A (en) | 1846-09-19 | Stbaw-cutter | ||
US106A (en) | 1915-08-24 | Specipication | ||
US5874082A (en) | 1992-07-09 | 1999-02-23 | Chiron Corporation | Humanized anti-CD40 monoclonal antibodies and fragments capable of blocking B cell proliferation |
US5397703A (en) | 1992-07-09 | 1995-03-14 | Cetus Oncology Corporation | Method for generation of antibodies to cell surface molecules |
NZ273504A (en) | 1993-10-01 | 1997-12-19 | Immunex Corp | Monoclonal antibodies (moabs) that specifically bind human cd40 molecules and cd40 ligand binding |
GB9425060D0 (en) | 1994-12-13 | 1995-02-08 | Univ Birmingham | Carcinoma treatment |
CN102416176A (en) | 1995-07-27 | 2012-04-18 | 基因技术股份有限公司 | Stabile isotonic lyophilized protein formulation |
WO1999015193A1 (en) | 1997-09-23 | 1999-04-01 | Rentschler Biotechnologie Gmbh & Co. Kg | LIQUID INTERFERON-β FORMULATIONS |
US6051228A (en) | 1998-02-19 | 2000-04-18 | Bristol-Myers Squibb Co. | Antibodies against human CD40 |
AU1590201A (en) | 1999-11-09 | 2001-06-06 | Chiron Corporation | Compositions and methods for treating autoimmune diseases and transplant rejections |
WO2001083755A2 (en) | 2000-04-28 | 2001-11-08 | La Jolla Institute For Allergy And Immunology | Human anti-cd40 antibodies and methods of making and using same |
US7063845B2 (en) | 2000-04-28 | 2006-06-20 | Gemini Science, Inc. | Human anti-CD40 antibodies |
US20030059427A1 (en) | 2000-04-28 | 2003-03-27 | Force Walker R. | Isolation and characterization of highly active anti-CD40 antibody |
AU6461201A (en) | 2000-07-12 | 2002-01-21 | Idec Pharma Corp | Treatment of b cell malignancies using combination of b cell depleting antibody and immune modulating antibody related applications |
KR20040023565A (en) | 2000-09-18 | 2004-03-18 | 아이덱 파마슈티칼즈 코포레이션 | Combination therapy for treatment of autoimmune diseases using b cell depleting/immunoregulatory antibody combination |
AU2002211366A1 (en) | 2000-10-02 | 2002-04-15 | Chiron Corporation | Human anti-cd40 antibodies |
WO2002060485A2 (en) | 2001-01-31 | 2002-08-08 | Idec Pharmaceuticals Corporation | Use of immunoregulatory antibodies in the treatment of neoplastic disorders |
WO2002078766A2 (en) | 2001-04-02 | 2002-10-10 | Genentech, Inc. | Combination therapy |
EP2011802A3 (en) | 2001-04-27 | 2009-04-15 | Kyowa Hakko Kirin Co., Ltd. | Anti-CD40 monoclonal antibody |
WO2003029296A1 (en) | 2001-10-02 | 2003-04-10 | Chiron Corporation | Human anti-cd40 antibodies |
AR039067A1 (en) | 2001-11-09 | 2005-02-09 | Pfizer Prod Inc | ANTIBODIES FOR CD40 |
CA2466931A1 (en) | 2001-11-26 | 2003-06-05 | Chiron Corporation | Antagonist anti-cd40 monoclonal antibody therapy for multiple sclerosis treatment |
US20080199471A1 (en) * | 2002-03-01 | 2008-08-21 | Bernett Matthew J | Optimized cd40 antibodies and methods of using the same |
WO2003074679A2 (en) * | 2002-03-01 | 2003-09-12 | Xencor | Antibody optimization |
EP3777880A1 (en) | 2003-02-10 | 2021-02-17 | Biogen MA Inc. | Immunoglobulin formulation and method of preparation thereof |
DE602004028270D1 (en) | 2003-11-04 | 2010-09-02 | Novartis Vaccines & Diagnostic | USE OF ANTAGONIST ANTI-CD40 ANTIBODIES FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA |
EP2301575A1 (en) | 2003-11-04 | 2011-03-30 | Novartis Vaccines and Diagnostics, Inc. | Methods of therapy for solid tumors expressing the CD40 cell-surface antigen |
US8277810B2 (en) | 2003-11-04 | 2012-10-02 | Novartis Vaccines & Diagnostics, Inc. | Antagonist anti-CD40 antibodies |
JP4810431B2 (en) | 2003-11-04 | 2011-11-09 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | Method for treating cancer associated with B cells |
EP2243492A1 (en) | 2003-11-04 | 2010-10-27 | Novartis Vaccines and Diagnostics, Inc. | Use of antagonist anti-cd40 monoclonal antibodies for treatment of multiple myeloma |
NZ548325A (en) * | 2003-12-25 | 2009-07-31 | Kirin Pharma Kk | Mutants of anti-CD40 antibody |
US20080057070A1 (en) * | 2004-11-04 | 2008-03-06 | Chiron Corporation | Antagonist Anti-Cd40 Monoclonal Antibodies and Methods for Their Use |
PL1889065T3 (en) | 2005-05-18 | 2013-12-31 | Novartis Ag | Methods for diagnosis and treatment of diseases having an autoimmune and/or inflammatory component |
US20090202531A1 (en) | 2005-11-01 | 2009-08-13 | Novartis Ag | Uses of anti-cd40 antibodies |
KR20080080639A (en) * | 2005-12-16 | 2008-09-04 | 제넨테크, 인크. | Anti-ox40l antibodies and methods using same |
SMP200800064B (en) | 2006-04-21 | 2009-11-06 | Novartis Ag | Pharmaceutical compositions of anti-cd40 antagonist antibodies |
EP1854810A1 (en) | 2006-05-09 | 2007-11-14 | PanGenetics B.V. | Deimmunized antagonistic anti-human CD40 monoclonal antibody from the ch5D12 antibody |
WO2008060705A2 (en) * | 2006-06-06 | 2008-05-22 | Genentech, Inc. | Anti-dll4 antibodies and methods using same |
EP3372237A1 (en) * | 2007-04-02 | 2018-09-12 | Genentech, Inc. | A klotho-beta agonist antibody for use in the treatment of diabetes mellitus or insulin resistance |
AU2008232506A1 (en) * | 2007-04-02 | 2008-10-09 | Genentech, Inc. | Biological markers predictive of rheumatoid arthritis response to B-cell antagonists |
EP4169951A1 (en) * | 2008-12-09 | 2023-04-26 | F. Hoffmann-La Roche AG | Anti-pd-l1 antibodies and their use to enhance t-cell function |
AR083847A1 (en) | 2010-11-15 | 2013-03-27 | Novartis Ag | FC VARIANTS (CONSTANT FRAGMENT) SILENCERS OF ANTI-CD40 ANTIBODIES |
US20140004131A1 (en) | 2012-05-04 | 2014-01-02 | Novartis Ag | Antibody formulation |
EP2967348B1 (en) | 2013-03-15 | 2022-03-23 | Synaptive Medical Inc. | Intelligent positioning system |
-
2011
- 2011-11-11 AR ARP110104221A patent/AR083847A1/en active IP Right Grant
- 2011-11-13 JO JOP/2011/0336A patent/JO3266B1/en active
- 2011-11-14 CN CN201610482804.9A patent/CN105949314B/en active Active
- 2011-11-14 LT LTEP11781571.2T patent/LT2640749T/en unknown
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Patent Citations (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4495285A (en) | 1981-10-30 | 1985-01-22 | Kimihiro Shimizu | Plasminogen activator derivatives |
US4495285B1 (en) | 1981-10-30 | 1986-09-23 | Nippon Chemiphar Co | |
US4609546A (en) | 1982-06-24 | 1986-09-02 | Japan Chemical Research Co., Ltd. | Long-acting composition |
US4766106A (en) | 1985-06-26 | 1988-08-23 | Cetus Corporation | Solubilization of proteins for pharmaceutical compositions using polymer conjugation |
WO1987004462A1 (en) | 1986-01-23 | 1987-07-30 | Celltech Limited | Recombinant dna sequences, vectors containing them and method for the use thereof |
US4881175A (en) | 1986-09-02 | 1989-11-14 | Genex Corporation | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
US5455030A (en) | 1986-09-02 | 1995-10-03 | Enzon Labs, Inc. | Immunotheraphy using single chain polypeptide binding molecules |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
EP0270799A1 (en) | 1986-10-27 | 1988-06-15 | Cetus Oncology Corporation | Pharmaceutical compositions of recombinant beta-interferon and formulation processes |
EP0268110A1 (en) | 1986-10-27 | 1988-05-25 | Cetus Oncology Corporation | Pharmaceutical compositions of recombinant interleukin-2 and formulation processes |
US5013653A (en) | 1987-03-20 | 1991-05-07 | Creative Biomolecules, Inc. | Product and process for introduction of a hinge region into a fusion protein to facilitate cleavage |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5132405A (en) | 1987-05-21 | 1992-07-21 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US5476786A (en) | 1987-05-21 | 1995-12-19 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5482858A (en) | 1987-05-21 | 1996-01-09 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
WO1989001036A1 (en) | 1987-07-23 | 1989-02-09 | Celltech Limited | Recombinant dna expression vectors |
EP0338841A1 (en) | 1988-04-18 | 1989-10-25 | Celltech Limited | Recombinant DNA methods, vectors and host cells |
US6180370B1 (en) | 1988-12-28 | 2001-01-30 | Protein Design Labs, Inc. | Humanized immunoglobulins and methods of making the same |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693761A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Polynucleotides encoding improved humanized immunoglobulins |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5674492A (en) | 1993-12-23 | 1997-10-07 | Immunex Corporation | Method of preventing or treating disease characterized by neoplastic cells expressing CD40 |
US5847082A (en) | 1994-03-03 | 1998-12-08 | Alexion Pharmaceuticals, Inc. | Terminal complement inhibitor fusion proteins |
WO1998056418A1 (en) | 1997-06-13 | 1998-12-17 | Genentech, Inc. | Stabilized antibody formulation |
US20020119151A1 (en) | 1997-06-20 | 2002-08-29 | Biogen, Inc. | CD154 blockade therapy for therapeutic protein inhibitor syndrome |
US20020006901A1 (en) | 1999-02-05 | 2002-01-17 | Aldo T. Iacono | Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease |
WO2005044306A2 (en) | 2003-11-04 | 2005-05-19 | Chiron Corporation | Use of antagonist anti-cd40 antibodies for treatment of autoimmune and inflammatory diseases and organ transplant rejection |
WO2006073443A2 (en) | 2004-04-27 | 2006-07-13 | Novartis Vaccines And Diagnostics, Inc. | Antagonist anti-cd40 monoclonal antibodies and methods for their use |
WO2008150494A1 (en) * | 2007-05-30 | 2008-12-11 | Xencor, Inc. | Methods and compositions for inhibiting cd32b expressing cells |
CA2759146A1 (en) * | 2009-04-20 | 2010-10-28 | Kyowa Hakko Kirin Co., Ltd. | Agonist anti-cd40 antibody |
Non-Patent Citations (60)
Title |
---|
"Peptide and Protein Drug Delivery", 1991, MARCEL DEKKER, INC. |
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY |
ABHINAV ET AL., JOURNAL OF CHROMATOGRAPHY, vol. 848, 2007, pages 28 - 37 |
BAUDINO ET AL., J. IMMUNOL., vol. 181, 2008, pages 6664 - 69 |
BIGAUD M, MAURER C, VEDRINE ET AL., J. PHARMACOL. TOXICOL. METHODS, vol. 50, no. 2, 2004, pages 153 - 9 |
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426 |
BLANCHER A, TISSEYRE P, DUTAUR M ET AL., IMMUNOGENETICS, vol. 58, no. 4, 2006, pages 269 - 82 |
BRENNAN ET AL., SCIENCE, vol. 229, 1985, pages 81 - 83 |
CAFISO, BIOCHEM BIOPHYS ACTA, vol. 649, 1981, pages 129 |
CHOTHIA ET AL., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917 |
COLIGAN ET AL., CURRENTPROTOCOLS IN IMMUNOLOGY, vol. 13, 1991, pages 12 |
DENTON ET AL., PEDIATR TRANSPLANT., vol. 2, 1998, pages 6 - 15 |
E. MEYERS, W. MILLER, COMPUT. APPL. BIOSCI., vol. 4, 1988, pages 11 - 17 |
EVANS ET AL., J : IMMUNOL., vol. 164, 2000, pages 688 - 697 |
F. AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 1987, GREENE PUBLISHING AND WLEY INTERSCIENCE |
FELSON ET AL., ARTHRITIS. RHEUM., vol. 38, 1995, pages 727 - 35 |
GABIZON ET AL., CANCER RESEARCH, vol. 42, 1982, pages 4734 |
GASCHEN L, KUNKLER A, MENNINGER K ET AL., VET. RADIOL. ULTRASOUND, vol. 42, no. 3, 2001, pages 259 - 64 |
GLENNIE ET AL., J. IMMUNOL., vol. 139, 1987, pages 2367 - 2375 |
GOEDDEL: "Gene Expression Technology. Methods in Enzymology", vol. 185, 1990, ACADEMIC PRESS |
HORTON HOLLY M ET AL: "Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 116, no. 16, 4 October 2010 (2010-10-04), pages 3004 - 3012, XP009146207, ISSN: 0006-4971, DOI: 10.1182/BLOOD-2010-01-265280 * |
HUSTON ET AL., PROC. NATL. ACAD. SCI., vol. 85, 1988, pages 5879 - 5883 |
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525 |
JONES, ADV. DRUG DELIVERY REV., vol. 10, 1993, pages 29 - 90 |
KABAT, E. A. ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NIH PUBLICATION NO. 91-3242 |
KABAT, E. A.: "Sequences of Proteins of Immunological Interest", 1991, NIH PUBLICATION NO. 91-3242 |
KARPOVSKY ET AL., J. EXP. MED., vol. 160, 1984, pages 1686 |
KNAUF ET AL., J. BIO. CHEM., vol. 263, 1988, pages 15064 - 15070 |
KOREN ET AL., CURR. PHARM. BIOTECHNOL., vol. 3, 2002, pages 349 - 60 |
KWEKKEBOOM ET AL., IMMUNOLOGY, vol. 79, 1993, pages 439 - 444 |
LAW CL, GREWAL IS., ADV. EXP. MED. BIOL. 2009, vol. 647, 2009, pages 8 - 36 |
LEDERMAN ET AL., CURR OPIN. HEMATOL., vol. 3, 1996, pages 77 - 86 |
LEVINE ET AL., J. PARENTERAL SCI. TECHNOL., vol. 45, no. 3, 1991, pages 160 - 165 |
LI ET AL., TRANSPLANTATION, vol. 86, no. 1, 2008, pages 10 - 15 |
LIU, MA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 8648 |
MORRISON, S., SCIENCE, vol. 229, 1985, pages 1202 |
NEEDLEMAN, WUNSCH, J. MOL, BIOL., vol. 48, 1970, pages 444 - 453 |
NOELLE, AGENTS ACTIONS, vol. 49, 1998, pages 17 - 22 |
PALMER BF, N. ENGL. J. MED, vol. 347, no. 16, 2002, pages 1256 - 1261 |
PAULUS, BEHRING INS. MITT. NO. 78, 1985, pages 118 - 132 |
POZNANSKY ET AL.: "Drug Delivery Systems", 1980, pages: 253 - 315 |
POZNANSKY, PHARM REVS, vol. 36, 1984, pages 277 |
PRESTA ET AL: "Engineering of therapeutic antibodies to minimize immunogenicity and optimize function", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER BV, AMSTERDAM, NL, vol. 58, no. 5-6, 7 August 2006 (2006-08-07), pages 640 - 656, XP005611419, ISSN: 0169-409X, DOI: 10.1016/J.ADDR.2006.01.026 * |
R.J. KAUFMAN, P.A. SHARP, MOL. BIOL., vol. 159, 1982, pages 601 - 621 |
REGELE H, EXNER M, WATSCHINGER B ET AL., NEPHROL. DIAL. TRANSPLANT, vol. 16, 2001, pages 2058 - 2066 |
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 327 |
SCHUSTER FL, RAMIREZ-AVILA L, CLIN. MICROBIOL. REV, vol. 21, no. 4, 2008, pages 626 - 38 |
SCHUTZE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 92, 1998, pages 8200 - 8204 |
SEGERER S, MACK M, REGELE H, KERJASCHKI D, SCH ÖNDORFF D., KIDNEY INT., vol. 56, 1999, pages 52 - 64 |
SETNIKAR ET AL., J. AM. PHARM. ASSOC., vol. 48, 1959, pages 628 |
SIBERIL ET AL: "FcgammaR: The key to optimize therapeutic antibodies?", CRITICAL REVIEWS IN ONCOLOGY / HEMATOLOGY, ELSEVIER SCIENCE IRELAND LTD., LIMERICK, IE, vol. 62, no. 1, 7 March 2007 (2007-03-07), pages 26 - 33, XP005912443, ISSN: 1040-8428, DOI: 10.1016/J.CRITREVONC.2006.12.003 * |
SOLEZ K, COLVIN RB, RACUSEN LC ET AL., AM. J. TRANSPLANT, vol. 8, no. 4, 2008, pages 753 - 60 |
STROHL, W., CURR. OPIN. BIOTECHNOL., vol. 20, no. 6, 2009, pages 685 - 691 |
SZOKA, ANN. REV. BIOPLAYS. ENG., vol. 9, 1980, pages 467 |
TAKEBE, Y. ET AL., MOL. CELL. BIOL., vol. 8, 1988, pages 466 - 472 |
URLAUB, CHASIN, PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 - 4220 |
VAN GESTEL ET AL., ARTHRITIS RHEUM., vol. 39, 1996, pages 34 - 40 |
VERHOEYEN ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 1536 |
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546 |
XIAN-LIANG LI ET AL: "Promises and Obstacles for the Blockade of CD40-CD40L Interactions in Allotransplantation", TRANSPLANTATION, vol. 86, no. 1, 1 July 2008 (2008-07-01), pages 10 - 15, XP055018800, ISSN: 0041-1337, DOI: 10.1097/TP.0b013e31817c4b97 * |
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