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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
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—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 immunoglobulin superfamily
  • C07K16/2818—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 immunoglobulin superfamily against CD28 or CD152
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/567—Framework region [FR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• • 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
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• B7-1 and B7-2 are also ligands for another molecule, CTLA4, present on the surface of activated T cells.
• the CD28 antagonist and/or antibody single variable domain has a CDRl sequence that is at least 50% identical to the CDRl sequence selected from the group consisting of DOM21-4, DOM21-18 and/or DOM21-28, and a CDR2 sequence that is at least 50% identical to the CDR2 sequence selected from the group consisting of DOM21-4, DOM21- 18 and/or DOM21-28, and a CDR3 sequence that is at least 50% identical to the CDR3 sequence of selected from the group consisting of DOM21-4, DOM21-18 and/or DOM21-28.
• Further acceptable or preferred ranges include, for example, 50 pM to 1 ⁇ M, 100 pM to 500 nM, 125 pM to 250 nM, 150 pM to 200 nM, 150 pM to 100 nM, and 200 pM to 50 nM.
• the PEG-linked polypeptide has an increased in vivo half-life relative to the same polypeptide composition lacking linked polyethylene glycol.
• the t ⁇ -half -life of the polypeptide composition is increased by 10% or more.
• the t ⁇ -half -life of the polypeptide composition is increased by 50% or more.
• the t ⁇ -half -life of the polypeptide composition is increased by 2X or more.
• the t ⁇ -half -life of the polypeptide composition is increased by 5X or more, e.g., 10X, 15X, 2OX, 25X, 30X, 40X, or more.
• the t ⁇ -half -life of the polypeptide composition is increased by 50X or more.
• a composition comprising an extended release formulation comprises an immunoglobulin single variable domain, including, but not limited to, a polypeptide comprising a an antibody single variable domain that binds CD28.
• the immunoglobulin single variable domain is a non-human mammalian antibody single variable domain.
• the immunoglobulin single variable domain is a human antibody single variable domain.
• the invention includes an antibody single variable domain polypeptide that binds to CD28, wherein the polypeptide has an amino acid sequence that is identical to the amino acid sequence of DOM21-4, or differs from the amino acid sequence of DOM21-4 at no more than 25 amino acid positions and has a CDRl sequence that is at least 50% identical to the CDRl sequence of DOM21-4, or has a CDR2 sequence that is at least 50% identical to the CDR2 sequence of DOM21-4, or has a CDR3 sequence that is at least 50% identical to the CDR3 sequence of DOM21-4.
• the invention also includes an antibody single variable domain polypeptide that binds CD28, wherein the dAb has an amino acid sequence that is identical to the amino acid sequence of DOM21-18, or differs from the amino acid sequence of DOM21-18 at no more than 25 amino acid positions and has a CDRl sequence that is at least 50% identical to the CDRl sequence of DOM21-18 and has a CDR2 sequence that is at least 50% identical to the CDR2 sequence of DOM21-18.
• the invention also includes an antibody single variable domain polypeptide that binds CD28, wherein the dAb has an amino acid sequence that is identical to the amino acid sequence of DOM21-28, or differs from the amino acid sequence of DOM21-28 at no more than 25 amino acid positions and has a CDRl sequence that is at least 50% identical to the CDRl sequence of DOM21-28 and has a CDR2 sequence that is at least 50% identical to the CDR2 sequence of DOM21-28.
• the antibody single variable domain polypeptide that binds to CD28 differs form the amino acid sequence of DOM21-28 at 25 or fewer amino acid positions, 20 or fewer amino acid positions, 15 or fewer amino acid positions, 10 or fewer amino acid positions, 5 or fewer amino acid positions, 2 or fewer amino acid positions, or as few as one amino acid position.
• a dual specific ligand comprising an anti-human CD28 antibody single variable domain and an anti-SA antibody single variable domain.
• the anti-CD28 variable domain or dAb comprises a universal framework.
• the anti-CD28 variable domain or dAb may also comprise a V H framework selected from the group consisting of DP47, DP45 and DP38; or a V L framework which is DPK9.
• the dual specific ligand or dAb can comprise a binding site for a generic ligand.
• the dAb monomer specific for CD28 has a dissociation constant (Ka) of 1x10 "7 M or less, as determined by surface plasmon resonance.
• a dual specific ligand comprising a first immunoglobulin single variable domain having a binding specificity to a first antigen and a second single variable domain having a binding activity to a second antigen, wherein the first antigen is CD28 and the second single variable domain is an Antigen Presenting Cell surface antigen or a T cell surface antigen.
• the Antigen Presenting Cell surface antigen can be selected from one of the group consisting of dendritic cell surface antigens, activated macrophage surface antigens, activated B cell surface antigens, co-stimulatory signal pathway surface antigens, and MHC antigens.
• the nanobody modulates, inhibits, prevents and/or blocks the interaction of B7-1 (CD80) with CD28.
• the nanobody modulates, inhibits, prevents and/or blocks the interaction of B7-1 with CD28 and the interaction of B7-2 with CD28.
• the nanobody modulates, inhibits, prevents and/or blocks the interaction of B7-1 with CD28, while the interaction of B7-2 with CD28 is not modulated, inhibited or prevented.
• the nanobody is chosen from the group consisting of SEQ ED NO's: 207-212.
• the amino acid sequence modulates, inhibits, prevents and/or blocks the interaction of B7-2 with CD28 and the interaction of B7-1 with CTLA4.
• the amino acid sequence modulates, inhibits, prevents and/or blocks the interaction of B7-1 with CD28 and the interaction of B7-2 with CD28.
• the amino acid sequence essentially consists of 4 framework regions (FRl to FR4, respectively) and 3 complementarity determining regions (CDRl to CDR3, respectively), in which: -CDRl is chosen from the group consisting of: a) the amino acid sequences of SEQ ID NO's: 335-340; b) amino acid sequences that have at least 80% amino acid identity with at least one of the amino acid sequences of SEQ ID NO's: 335-340; c) amino acid sequences that have 3, 2, or 1 amino acid difference with at least one of the amino acid sequences of SEQ ID NO's: 335-340; and CDR2 is chosen from the group consisting of: d) the amino acid sequences of SEQ ID NO's: 347-352; e) amino acid sequences that have at least 80% amino acid identity with at least one of the amino acid sequences of SEQ ID NO's: 347-352; f) amino acid sequences that have 3, 2, or 1 amino acid difference with at least one of the amino acid sequences
• Figure 2 shows ELISAs of soluble monoclonal antibody single variable domain binding to recombinant human CD28/Fc Chimera and Fc control coated plates.
• Figure 3 shows ELISAs of soluble monoclonal antibody single variable domain binding in the presence or absence of protein A to recombinant human CD28/Fc Chimera and Fc control coated plates.
• Figure 9 shows preferred combinations of CDR sequences, preferred combinations of framework sequences, and preferred combinations of framework and CDR sequences for Nanobodies against CD28.
• "retains activity” refers to a level of activity of a PEG-linked antibody single variable domain which is at least 10% of the level of activity of a non-PEG-linked antibody single variable domain, including at least 20%, 30%, 40%, 50%, 60%, 70%, 80% and up to 90%, including up to 95%, 98%, and up to 100% of the activity of a non-PEG-linked antibody single variable domain comprising the same antigen- binding domain or domains.
• a "generic ligand” is a ligand that binds a substantial proportion of functional members in a given repertoire, e.g., in a phage display library.
• the same generic ligand can bind many members of the repertoire regardless of their target ligand specificities.
• the presence of a functional generic ligand binding site indicates that the repertoire member is expressed and folded correctly.
• binding of the generic ligand to its binding site provides a method for preselecting functional polypeptides from a repertoire of polypeptides.
• Generic ligands include, for example, Protein A, Protein G and Protein L.
• the first and the second variable domains of such a the multi-specific polypeptide may be on the same polypeptide chain. Alternatively they may be on separate polypeptide chains. In the case that they are on the same polypeptide chain they may be linked by a linker, which is preferentially a peptide sequence, as described above.
• V-gene repertoires are used variation in polypeptide sequence is, in an aspect, located within the structural loops of the variable domains.
• the polypeptide sequences of either antibody single variable domain may be altered by DNA shuffling or by mutation.
• DNA shuffling is known in the art and taught, for example, by Stemmer, 1994, Nature 370: 389-391 and U.S. Patent No. 6,297,053, both of which are incorporated herein by reference.
• Other methods of mutagenesis are well known to those of skill in the art.
• vector refers to a discrete element that is used to introduce heterologous DNA into cells for the expression and/or replication thereof.
• Methods by which to select or construct and, subsequently, use such vectors are well known to one of ordinary skill in the art. Numerous vectors are publicly available, including bacterial plasmids, bacteriophage, artificial chromosomes, and episomal vectors. Such vectors may be used for simple cloning and mutagenesis; alternatively gene expression vector is employed.
• a vector of use as disclosed herein may be selected to accommodate a polypeptide coding sequence of a desired size, typically from 0.25 kilobase (kb) to 40 kb or more in length.
• Plasma proteins such as fibrin, ⁇ -2 macroglobulin, serum albumin, fibrinogen A, fibrinogen B, serum amyloid protein A, heptaglobin, profilin, ubiquitin, uteroglobulin, and ⁇ -2-microglobulin;
• angiogenic growth factors including acidic fibroblast growth factor (FGF-I), basic fibroblast growth factor (FGF-2), vascular endothelial growth factor / vascular permeability factor (VEGF /VPF), transforming growth factor-a (TGF a), tumor necrosis factor-alpha (TNF- ⁇ ), angiogenin, interleukin-3 (IL-3), interleukin-8 (IL-8), platelet-derived endothelial growth factor (PD-ECGF), placental growth factor (PlGF), midkine platelet-derived growth factor-BB (PDGF), fractalkine.
• FGF-I acidic fibroblast growth factor
• FGF-2 basic fibroblast growth factor
• VEGF /VPF vascular endothelial growth factor / vascular permeability factor
• TGF a tumor necrosis factor-alpha
• IL-3 interleukin-3
• IL-8 interleukin-8
• PD-ECGF platelet-derived endothelial growth
• a PEG- or other polymer-linked antibody single variable domain monomer or multimer is degraded by no more than 10% when exposed to pepsin at pH 2.0 for 30 minutes, in an aspect, no more than 5%, and in another aspect, not degraded at all.
• a PEG- or other polymer-linked antibody single variable domain multimer e.g., hetero- or homodimer, trimer, tetramer, octamer, etc.
• a PEG- or other polymer-linked antibody single variable domain multimer e.g., hetero- or homodimer, trimer, tetramer, octamer, etc.
• Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• psoriasis is ameliorated by administering to an individual having psoriasis, an antagonist anti-CD28 dAb, or composition thereof, described herein.
• Chronic rejection is a prolonged process of declining allograft function. Chronic rejection probably begins at the time of transplantation, but may take months or years to manifest clinically according to a Medscape article published on the web at medscape.com/viewarticle/436533_12. While the clinical and biochemical signs are organ- specific, the result of chronic rejection is the same for all solid organ allografts. Slowly deteriorating graft function (DGF) caused by fibrosis of the graft parenchyma and widespread arteriopathy are the hallmarks of chronic rejection that lead to loss of function and eventual graft loss. T cells and B cells contribute to the damage characteristic of chronic rejection, Demetris AJ, Duquesnor RJ, Fung JJ, et al.
• DGF slowly deteriorating graft function
• one aspect of the instant invention is to ameliorate an autoimmune diseases generated by administration of TCR-transgenic T cells uniformly expressing an identifiable TCR of known peptide/MHC specificity to a specific autoantigen, by administering an antagonist anti-CD28 dAb described herein.
• the anti-CD28 dab is divalent, binding to both CD28 and to said TCR.
• Antibody single variable domains with CD28 binding properties were selected from a library of VH and VK polypeptides. Selections were carried out with recombinant human CD28/Fc Chimera (R&D Systems, Abingdon, UK). The dAb library used for selections was based on a single human VH framework (V3-23 [locus] DP47 [V Base Entry] and JH4b) and a single human VL framework (012/02 [locus] DP ⁇ 9 [V Base Entry] and J ⁇ l).
• CD28 specific clones were identified by comparison to a control plate coated with Fc alone (see Figure 3 for example of soluble ELISA). All specific clones were DNA sequenced and initially 28 unique clones were identified (see below for sequences). An additional two plates of antibody single variable domain supernatants were screened for binding to CD28-Fc by BIAcore analysis (GE Healthcare, UK). From this screening, an additional 30 unique sequences were identified (see below for sequences).

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