EP1545608A2 - Corps mimetiques mammaliens a deletion ch1, compositions, procedes et utilisations - Google Patents

Corps mimetiques mammaliens a deletion ch1, compositions, procedes et utilisations

Info

Publication number
EP1545608A2
EP1545608A2 EP03742272A EP03742272A EP1545608A2 EP 1545608 A2 EP1545608 A2 EP 1545608A2 EP 03742272 A EP03742272 A EP 03742272A EP 03742272 A EP03742272 A EP 03742272A EP 1545608 A2 EP1545608 A2 EP 1545608A2
Authority
EP
European Patent Office
Prior art keywords
deleted mimetibody
chi
drug
ofthe
hydrochloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03742272A
Other languages
German (de)
English (en)
Other versions
EP1545608A4 (fr
Inventor
George A. Heavner
David M. Knight
John Ghrayeb
Bernard J. Scallon
Thomas C. Nesspor
Karen A. Kutoloski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Biotech Inc
Original Assignee
Centocor Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centocor Inc filed Critical Centocor Inc
Publication of EP1545608A2 publication Critical patent/EP1545608A2/fr
Publication of EP1545608A4 publication Critical patent/EP1545608A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C07K2318/00—Antibody mimetics or scaffolds
    • C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention relates to mammalian CHI -deleted mimetibodies, specified portions and variants specific for bologically active proteins, fragment or ligands, CHI -deleted mimetibody encoding and complementary nucleic acids, host cells, and methods of making and using thereof, including therapeutic formulations, administration and devices.
  • Recombinant proteins are an emerging class of therapeutic agents. Such recombinant therapeutics have engendered advances in protein formulation and chemical modification. Such modifications can potentially enhance the therapeutic utility of therapeutic proteins, such as by increaseing half lives (e.g., by blocking their exposure to proteolytic enzymes), enhancing biological activity, or reducing unwanted side effects.
  • One such modification is the use of immunoglobulin fragments fused to receptor proteins, such as enteracept.
  • Therapeutic proteins have also been constructed using the Fc domain to attempt to provide a longer half-life or to incorporate functions such as Fc receptor binding, protein A binding, and complement fixation.
  • the present invention provides isolated human CHI -deleted mimetibodies, including modified immunoglobulins, cleavage products and other specified portions and variants thereof, as well as CH1- deleted mimetibody compositions, encoding or complementary nucleic acids, vectors, host cells, compositions, formulations, devices, transgenic animals, transgenic plants, and methods of making and using thereof, as described and/or enabled herein, in combination with what is known in the art.
  • the present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art.
  • the CHI deleted mimetibody can optionally comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence.
  • a pair of a CH3-CH2-hinge-partial J sequence-linker-therapeutic peptide with an option N-terminal antibody sequence the pair optionally linked by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond.
  • a CHI deleted mimetibody comprises formula (I):
  • VI is at least one portion of an N-terminus of an immunoglobulin variable region
  • Pep is at least one bioactive peptide
  • Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties
  • V2 is at least one portion of a C- terminus of an immunoglobulin variable region
  • pHinge is at least a portion of an immunoglobulin variable hinge region
  • CH2 is at least a portion of an immunoglobulin CH2 constant region
  • CH3 is at least a portion of an immunoglobulin CH3 constant region
  • n and m can be an integer between 1 and 10, mimicing different types of immunoglobulin molecules, e.g., but not limited to IgGl, IgG2, IgG3, IgG4, IgA, IgM, Ig
  • a CHI -deleted mimetibody of the present invention mimics at least a portion of an antibody or immnuoglobulin structure or function with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities.
  • the various portions ofthe antibody and therapeutic peptide portions of at least one CHI- deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art.
  • At least one CHI -deleted mimetibody or specified portion or variant ofthe invention mimics the binding ofthe Pep portion ofthe mimetibody to at least one ligand, or has at least one biological activity of, at least one protein, subunit, fragment, portion or any combination thereof.
  • the present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art, wherein the CHI -deleted mimetibody or specified portion or variant has at least one activity, such as, but not limited to known biological activities of at least one bioactive peptide or polypeptide corresponding to the Pep portion of formula I.
  • a CHI -deleted mimetibody can thus be screened for a corresponding activity according to known methods, such as at least one neutralizing activity towards a protein or fragment thereof.
  • the present invention provides at least one isolated mammalian CHI -deleted mimetibody, comprising at least one Pep(n) region comprising at least a bilogically active portion of at least one of SEQ ID NOS: 1-979, or optionally with one or more substitutions, deletions or insertions as described herein and/or as known in the art.
  • the present invention provides at least one isolated mammalian CHI -deleted mimetibody, wherein the CHI-deleted mimetibody specifically binds at least one epitope comprising at least 1-3, to the entire amino acid sequence of at least one ligand or binding region which ligand binds to at least a portion of at least one of SEQ ID NOS: 1-1109, or optionally with one or more substitutions, deletions or insertions as described herein or as known in the art.
  • the at least one CHI -deleted mimetibody can optionally further comprise at least one characteristic selected from (i) bind at least one protein with an affinity of at least 10 "9 M, at least 10 "10 M, at least 10 "u M, or at least 10 "12 M; and/or (ii) substantially neutralize at least one activity of at least one protein or portion thereof.
  • the present invention provides, in one aspect, isolated nucleic acid molecules comprising, complementary, having significant identity or hybridizing to, a polynucleotide encoding specific ' mimetibodies or specified portions or variants thereof, comprising at least one specified sequence, domain, portion or variant thereof.
  • the present invention further provides recombinant vectors comprising at least one of said isolated CHI -deleted mimetibody nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such CHI-deleted mimetibody nucleic acids, vectors and/or host cells.
  • an isolated nucleic acid encoding at least one isolated mammalian CH1- deleted mimetibody; an isolated nucleic acid vector comprising the isolated nucleic acid, and/or a prokaryotic or eukaryotic host cell comprising the isolated nucleic acid.
  • the host cell can optionally be at least one selected from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2, 653, SP2/0, 293, HeLa, myeloma, or lymphoma cells, or any derivative, immortalized or transformed cell thereof.
  • Also provided is a method for producing at least one CHI -deleted mimetibody comprising translating the CHI -deleted mimetibody encoding nucleic acid under conditions in vitro, in vivo or in situ, such that the CHI -deleted mimetibody is expressed in detectable or recoverable amounts.
  • the present invention also provides at least one composition
  • a composition comprising (a) an isolated CH1- deleted mimetibody or specified portion or variant encoding nucleic acid and/or CHI -deleted mimetibody as described herein; and (b) a suitable carrier or diluent.
  • the carrier or diluent can optionally be pharmaceutically acceptable, according to known methods.
  • the composition can optionally further comprise at least one further compound, protein or composition.
  • compositions comprising at least one isolated mammalian CHI -deleted mimetibody and at least one pharmaceutically acceptable carrier or diluent.
  • the composition can optionally further comprise an effective amount of at least one compound or protein selected from at least one of a detectable label or reporter, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NTHE), an analgesic, an anesthetic, a sedative, a local anethetic, a
  • the present invention further provides at least one anti-idiotype antibody to at least one CH1- deleted mimetibody ofthe present invention.
  • the anti-idiotype antibody includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to at least one complimetarity determing region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a CH1- deleted mimetibody ofthe present invention.
  • CDR complimetarity determing region
  • a CHI -deleted mimetibody ofthe invention can include or be derived from any mammal, such as but not limited to a human, a mouse, a rabbit, a rat, a rodent, a primate, and the like.
  • the present invention further provides an anti-idiotype antibody or fragment that specifically binds at least one CHI deleted mimetibody ofthe present invention.
  • the present invention provides, in one aspect, isolated nucleic acid molecules comprising, complementary, or hybridizing to, a polynucleotide encoding at least one CHI -deleted mimetibody anti-idiotype antibody, comprising at least one specified sequence, domain, portion or variant thereof.
  • the present invention further provides recombinant vectors comprising said CHI -deleted mimetibody anti-idiotype antibody encoding nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such anti-idiotype antiobody nucleic acids, vectors and/or host cells.
  • the present invention also provides at least one method for expressing at least one CH1- deleted mimetibody or specified portion or variant, or CHI -deleted mimetibody anti-idiotype antibody, in a host cell, comprising culturing a host cell as described herein and/or as known in the art under conditions wherein at least one CHI -deleted mimetibody or specified portion or variant, or anti- idiotype antibody is expressed in detectable and/or recoverable amounts.
  • the present invention further provides at least one CHI -deleted mimetibody, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of at least one of a bone and joint disorder, cardiovascular disoder, a dental or oral disorder, a dermatologic disorder, an ear, nose or throat disorder, an endocrine or metabolic disorder, a gastrointestinal disorder, a gynecologic disorder, a hepatic or biliary disorder, a an obstetric disorder, a hematologic disorder, an immunologic or allergic disorder, an infectious disease, a musculoskeletal disorder, a oncologic disorder, a neurologic disorder, a nutritrional disorder, an opthalmologic disorder, a pediatric disorder, a poisoning disorder, a psychiatric disorder, a renal disorder, a pulmonary disorder, or any other known disorder.
  • the present invention further provides at least one CHI -deleted mimetibody, specified portion or variant in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of, at least one immune, cardiovascular, infectious, malignant, and/or neurologic disease in a cell, tissue, organ, animal or patient and/or, as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in the art and/or as described herein.
  • the present invention also provides at least one composition, device and/or method of delivery of a therapeutically or prophylactically effective amount of at least one CHI -deleted mimetibody or specified portion or variant, according to the present invention.
  • the present invention also provides at least one composition
  • a composition comprising (a) an isolated CH1- deleted mimetibody encoding nucleic acid and/or CHI -deleted mimetibody as described herein; and (b) a suitable carrier or diluent.
  • the carrier or diluent can optionally be pharmaceutically acceptable, according to known carriers or diluents.
  • the composition can optionally further comprise at least one further compound, protein or composition.
  • the present invention further provides at least one CHI -deleted mimetibody method or composition, for administering a therapeutically effective amount to modulate or treat at least one protein related condition in a cell, tissue, organ, animal or patient and/or, prior to, subsequent to, or during a related condition, as known in the art and/or as described herein.
  • the present invention also provides at least one composition, device and/or method of delivery of a therapeutically or prophylactically effective amount of at least one CHI -deleted mimetibody, according to the present invention.
  • the present invention further provides at least one CHI -deleted mimetibody method or composition, for diagnosing at least one protein related condition in a cell, tissue, organ, animal or patient and/or, prior to, subsequent to, or during a related condition, as known in the art and/or as described herein.
  • the present invention also provides at least one composition, device and/or method of delivery for diagnosing of at least one CHI -deleted mimetibody, according to the present invention. Also provided is a method for diagnosing or treating a disease condition in a cell, tissue, organ or animal, comprising
  • composition comprising an effective amount of at least one isolated mammalian CHI -deleted mimetibody ofthe invention with, or to, the cell, tissue, organ or animal.
  • the method can optionally further comprise using an effective amount of 0.001-50 mg/kilogram ofthe cells, tissue, organ or animal.
  • the method can optionally further comprise using the contacting or the administrating by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.
  • parenteral subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary,
  • the method can optionally further comprise administering, prior, concurrently or after the (a) contacting or administering, at least one composition comprising an effective amount of at least one compound or protein selected from at least one of a detectable label or reporter, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug
  • NSAID an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.
  • a medical device comprising at least one isolated mammalian CHI -deleted mimetibody ofthe invention, wherein the device is suitable to contacting or administerting the at least one CHI -deleted mimetibody by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.
  • an article of manufacture for human pharmaceutical or diagnostic use comprising packaging material and a container comprising a solution or a lyophilized form of at least one isolated mammalian CHI-deleted mimetibody ofthe present invention.
  • the article of manufacture can optionally comprise having the container as a component of a parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal
  • Also provided is a method for producing at least one isolated mammalian CHI -deleted mimetibody ofthe present invention comprising providing a host cell or transgenic animal or transgenic plant or plant cell capable of expressing in recoverable amounts the CHI -deleted mimetibody. Further provided in the present invention is at least one CHI -deleted mimetibody produced by the above method. The present invention further provides any invention described herein.
  • the present invention provides isolated, recombinant and/or synthetic mimetibodies or specified portions or variants, as well as compositions and encoding nucleic acid molecules comprising at least one polynucleotide encoding at least one CHI -deleted mimetibody.
  • Such mimetibodies or specified portions or variants ofthe present invention comprise specific CHI -deleted mimetibody sequences, domains, fragments and specified variants thereof.
  • the present invention also provides methods of making and using said nucleic acids and mimetibodies or specified portions or variants, including therapeutic compositions, methods and devices.
  • the present invention also provides at least one isolated CHI -deleted mimetibody or specified portion or variant as described herein and/or as known in the art.
  • the CHI deleted mimetibody can optionally comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence.
  • a CHI deleted mimetibody comprises formula (I):
  • VI is at least one portion of an N-terminus of an immunoglobulin variable region
  • Pep is at least one bioactive peptide
  • Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties
  • V2 is at least one portion of a C- terminus of an immunoglobulin variable region
  • pHinge is at least a portion of an immunoglobulin variable hinge region
  • CH2 is at least a portion of an immunoglobulin CH2 constant region
  • CH3 is at least a portion of an immunoglobulin CH3 constant region
  • n and m can be an integer between 1 and 10, mimicing different types of immunoglobulin molecules, e.g., but not limited to IgGl, IgG2, IgG3, IgG4, IgA, IgM, Ig
  • a CHI-deleted mimetibody ofthe present invention mimics an antibody structure with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities.
  • the various portions ofthe antibody and therapeutic peptide portions of at least one CHI -deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art.
  • a "CHI-deleted mimetibody,” “CHI-deleted mimetibody portion,” or “CHI- deleted mimetibody fragment” and/or “CHI -deleted mimetibody variant” and the like mimics, has or simulates at least one ligand binding or at least one biological activity of at least one protein, such as but not limited to at least one biologically active portion of at least one of SEQ ID NOS: 1-979, in vitro, in situ and/or preferably in vivo.
  • a suitable CHI-deleted mimetibody, specified portion or variant ofthe present invention can bind at least one protein ligand and includes at least one protein ligand, receptor, soluble receptor, and the like.
  • a suitable CHI -deleted mimetibody, specified portion, or variant can also modulate, increase, modify, activate, at least one protein receptor signaling or other measurable or detectable activity.
  • Mimetibodies useful in the methods and compositions ofthe present invention are characterized by suitable affinity binding to protein ligands or receptors and optionally and preferably having low toxicity.
  • a CHI -deleted mimetibody where the individual components, such as the portion of variable region, constant region (without a CHI portion) and framework, or any portion thereof (e.g., a portion ofthe J, D or V rgions ofthe variable heavy or light chain; the hinge region, the constant heavy chain or light chain, and the like) individually and/or collectively optionally and preferably possess low immunogenicity, is useful in the present invention.
  • the mimetibodies that can be used in the invention are optionally characterized by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other undefined properties, may contribute to the therapeutic results achieved.
  • Low immunogenicity is defined herein as raising significant HAMA, HACA or HAHA responses in less than about 75%, or preferably less than about 50, 45, 40, 35, 30, 35, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, and/or 1 % ofthe patients treated and/or raising low titres in the patient treated (less than about 300, preferably less than about 100 measured with a double antigen enzyme immunoassay) (see, e.g., Elliott et al, Lancet 344:1125-1127 (1994)).
  • the isolated nucleic acids ofthe present invention can be used for production of at least one
  • CHI -deleted mimetibody fragment or specified variant thereof, which can be used to effect in an cell, tissue, organ or animal (including mammals and humans), to modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of, at least one protein related condition, selected from, but not limited to, at least one of an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, an anemia; an immune/autoimmune; and/or an cancerous/infecteous, as well as other known or specified protein related conditions.
  • Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one CHI -deleted mimetibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduction in symptoms, effects or mechanisms.
  • the effective amount can comprise an amount of about 0.0001 to 500 mg/kg per single or multiple administration, or to achieve a serum concentration of 0.0001-5000 ⁇ g ml serum concentration per single or multiple adminstration, or any effective range or value therein, as done and determined using known methods, as described herein or known in the relevant arts.
  • the CHI deleted mimetibody can comprise at least one CH3 region directly linked with at least one CH2 region directly linked with at least one hinge region or fragment thereof directly linked with at least one partial V region, directly linked with an optional linker sequence, directly linked to at least one therapeutic peptide, optionally further directly linked with at least a portion of at least one variable antibody sequence.
  • the pair can be linked by association or covalent linkage, such as, but not limited to, a Cys-Cys disulfide bond.
  • a CHI-deleted mimetibody ofthe present invention mimics an antibody structure with its inherent properties and functions, while providing a therapeutic peptide and its inherent or acquired in vitro, in vivo or in situ properties or activities.
  • the various portions ofthe antibody and therapeutic peptide portions of at least one CHI -deleted mimetibody ofthe present invention can vary as described herein in combinatoin with what is known in the art.
  • mimetibodies comprise at least one ligand binding region (LBR) that corresponds to at least one portion of at least one complementarity determining region (CDR, e.g., CDR1, CDR2 or CDR3 of HC or LC variable region) of at least one antibody or fragment or portion thereof where at least one ligand protein is inserted into or replaces at least a portion of at least one CDR ofthe antibody or portion thereof.
  • LBR ligand binding region
  • CDR complementarity determining region
  • Such mimetibodies ofthe present invention thus provide at least one suitable property as compared to known proteins, such as, but not limited to, at least one of increased half-life, increased activity, more specific activity, increased avidity, increased or decreased off rate, a selected or more suitable subset of activities, less immurgiicity, increased quality or duration of at least one desired therapeutic effect, less side effects, and the like.
  • Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as described herein.
  • papain or pepsin cleavage can generate CHI -deleted mimetibody Fab or F(ab') 2 fragments, respectively.
  • Other proteases with the requisite substrate specificity can also be used to generate Fab or F(ab') 2 fragments or portions thereof.
  • Mimetibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream ofthe natural stop site.
  • a chimeric gene encoding a F(ab') 2 heavy chain portion can be designed to include DNA sequences encoding the
  • mimetibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.
  • a nucleic acid encoding the variable and constant regions of a human antibody chain can be expressed to produce a contiguous protein for use in mimetibodies ofthe present invention. See, e.g., Ladner et al, U.S. Patent No. 4,946,778 and Bird,
  • human mimetibody refers to an antibody in which substantially every part ofthe protein (e.g., LBR, framework, C L , C H domains (e.g., C H 1, C H 2, C H 3), hinge, (V L , V H )) is expected to be substantially non-immunogenic, with only minor sequence changes or variations. Such changes or variations optionally and preferably retain or reduce the immunogenicity in humans relative to non-modified human antibodies, or mimetibodies ofthe prsent invention.
  • a human antibody and corresponding CHI -deleted mimetibody ofthe present invention is distinct from a chimeric or humanized antibody.
  • a human antibody and CHI -deleted mimetibody can be produced by a non-human animal or cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes, and for a CHI-deleted mimetibody, wherein at least one Ig CDR is replaced by an LBR of at least one ligand protein or fragment.
  • a non-human animal or cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes, and for a CHI-deleted mimetibody, wherein at least one Ig CDR is replaced by an LBR of at least one ligand protein or fragment.
  • Human mimetibodies that are specific for at least one protein ligand or receptor thereof can be designed against an appropriate ligand, such as isolated and/or protein receptor or ligand, or a portion thereof (including synthetic molecules, such as synthetic peptides). Preparation of such mimetibodies are performed using known techniques to identify and characterize ligand binding regions or sequences of at least one protein or portion thereof.
  • a CHI deleted mimetibody comprises formula (I): (Vl(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where VI is at least one portion of an N-terminus of an immunoglobulin variable region, Pep is at least one bioactive peptide, Flex is polypeptide that provides structural flexablity by allowing the mimietibody to have alternative orientations and binding properties, V2 is at least one portion of a C- terminus of an immunoglobulin variable region, pHinge is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region, n and m can be an integer between 1 and
  • CHI -deleted mimetibody or specified portion or variant ofthe present invention is produced by at least one cell line, mixed cell line, immortalized cell or clonal population of immortalized and/or cultured cells.
  • Immortalized protein producing cells can be produced using suitable methods.
  • the at least one CHI-deleted mimetibody or specified portion or variant is generated by providing nucleic acid or vectors comprising DNA derived or having a substantially similar sequence to, at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement, and which further comprises a mimetibody structure as described herein, e.g., but not limited to Formula (I), wherein known portions of :C- and N- termiinal variable regions can be used for VI and V2, hinge regions for pHinge, CH2 for CH2 and CH3 for CH3, as known in the art.
  • Formula (I) wherein known portions of :C- and N- termiinal variable regions can be used for VI and V2, hinge regions for pHinge, CH2 for CH2 and CH3 for CH3, as known in the art.
  • the term "functionally rearranged,” as used herein refers to a segment of nucleic acid from an immunoglobulin locus that has undergone V(D)J recombination, thereby producing an immunoglobulin gene that encodes an immunoglobulin chain (e.g., heavy chain, light chain), or any portion thereof.
  • a functionally rearranged immunoglobulin gene can be directly or indirectly identified using suitable methods, such as, for example, nucleotide sequencing, hybridization (e.g., Southern blotting, Northern blotting) using probes that can anneal to coding joints between gene segments or enzymatic amplification of immunoglobulin genes (e.g., polymerase chain reaction) with primers that can anneal to coding joints between gene segments.
  • suitable methods such as, for example, nucleotide sequencing, hybridization (e.g., Southern blotting, Northern blotting) using probes that can anneal to coding joints between gene segments or enzymatic amplification of immunoglob
  • Mimetibodies, specified portions and variants ofthe present invention can also be prepared using at least one CHI -deleted mimetibody or specified portion or variant encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce such mimetibodies or specified portions or variants in their milk.
  • Such animals can be provided using known methods as applied for antibody encoding sequences. See, e.g., but not limited to, US patent nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of which is entirely incorporated herein by reference.
  • Mimetibodies, specified portions and variants ofthe present invention can additionally be prepared using at least one CHI -deleted mimetibody or specified portion or variant encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to tobacco and maize) that produce such mimetibodies, specified portions or variants in the plant parts or in cells cultured therefrom.
  • transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, e.g., using an inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and references cited therein.
  • transgenic maize have been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and references cited therein.
  • Antibodies have also been produced in large amounts from transgenic plant seeds including antibody fragments, such as single chain mimetibodies (scFv's), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and references cited therein.
  • mimetibodies, specified portions and variants ofthe present invention can also be produced using transgenic plants, according to know methods. See also, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., Plant Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994); and references cited therein. The above references are entirely incorporated herein by reference.
  • the mimetibodies ofthe invention can bind human protein ligands with a wide range of affinities (K D ).
  • At least one human CHI-deleted mimetibody ofthe present invention can optionally bind at least one protein ligand with high affinity.
  • at least one CHI -deleted mimetibody ofthe present invention can bind at least one protein ligand with a K D equal to or less than about 10 "9 M or, more preferably, with a K D equal to or less than about 0.1-9.9 (or any range or value therein) X 10 "10 M, 10 "11 , 10 "12 , 10 "13 or any range or value therein.
  • the affinity or avidity of a CHI -deleted mimetibody for at least one protein ligand can be determined experimentally using any suitable method, e.g., as used for determing antibody-antigen binding affinity or avidity.
  • any suitable method e.g., as used for determing antibody-antigen binding affinity or avidity.
  • the measured affinity of a particular CHI -deleted mimetibody-ligand interaction can vary if measured under different conditions (e.g., salt concentration, pH).
  • affinity and other ligand-binding parameters e.g., K D , K a , K
  • K D , K a , K affinity and other ligand-binding parameters
  • nucleotide sequences encoding at least 90- 100% ofthe contiguous amino acids of at least one of SEQID NOS:1-1009 as well as at least one portion of an antibody, wherein the above sequences are inserted as the Pep sequence of Formula (I) to provide a CHI -deleted mimetibody ofthe present invention, further comprising specified fragments, variants or consensus sequences thereof, or a deposited vector comprising at least one of these sequences
  • a nucleic acid molecule ofthe present invention encoding at least one CHI-deleted mimetibody or specified portion or variant can be obtained using methods described herein or as known in the art.
  • Nucleic acid molecules ofthe present invention can be in the form of RNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA, including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combination thereof.
  • the DNA can be triple-stranded, double-stranded or single-stranded, or any combination thereof. Any portion of at least one strand ofthe DNA or RNA can be the coding strand, also known as the sense strand, or it can be the non-coding strand, also referred to as the anti-sense strand.
  • Isolated nucleic acid molecules ofthe present invention can include nucleic acid molecules comprising an open reading frame (ORF), optionally with one or more introns, nucleic acid molecules comprising the coding sequence for a CHI-deleted mimetibody or specified portion or variant; and nucleic acid molecules which comprise a nucleotide sequence substantially different from those described above but which, due to the degeneracy ofthe genetic code, still encode at least one CH1- deleted mimetibody as described herein and/or as known in the art.
  • ORF open reading frame
  • nucleic acid molecules comprising the coding sequence for a CHI-deleted mimetibody or specified portion or variant
  • the genetic code is well known in the art.
  • nucleic acid variants that code for specific CHI -deleted mimetibody or specified portion or variants of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention.
  • nucleic acid molecules ofthe present invention which comprise a nucleic acid encoding a CHI -deleted mimetibody or specified portion or variant can include, but are not limited to, those encoding the amino acid sequence of a CHI -deleted mimetibody fragment, by itself; the coding sequence for the entire CHI -deleted mimetibody or a portion thereof; the coding sequence for a CHI -deleted mimetibody, fragment or portion, as well as additional sequences, such as the coding sequence of at least one signal leader or fusion peptide, intron, non-coding 5' and 3' sequences, such as the transcribed, non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (for example - ribosome binding and stability of mRNA); an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities.
  • sequence encoding a CHI -deleted mimetibody or specified portion or variant can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification ofthe fused CHI-deleted mimetibody or specified portion or variant comprising a CHI-deleted mimetibody fragment or portion.
  • the present invention provides isolated nucleic acids that hybridize under selective hybridization conditions to a polynucleotide disclosed herein, or others disclosed herein, including specified variants or portions thereof.
  • the polynucleotides of this embodiment can be used for isolating, detecting, and/or quantifying nucleic acids comprising such polynucleotides.
  • Low or moderate stringency hybridization conditions are typically, but not exclusively, employed with sequences having a reduced sequence identity relative to complementary sequences.
  • Moderate and high stringency conditions can optionally be employed for sequences of greater identity.
  • Low stringency conditions allow selective hybridization of sequences having about 40-99% sequence identity and can be employed to identify orthologous or paralogous sequences.
  • polynucleotides of this invention will encode at least a portion of a CHI -deleted mimetibody or specified portion or variant encoded by the polynucleotides described herein.
  • the polynucleotides of this invention embrace nucleic acid sequences that can be employed for selective hybridization to a polynucleotide encoding a CHI-deleted mimetibody or specified portion or variant of the present invention. See, e.g., Ausubel, supra; CoUigan, supra, each entirely incorporated herein by reference. Construction of Nucleic Acids
  • the isolated nucleic acids ofthe present invention can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, or combinations thereof, as well-known in the art.
  • the nucleic acids can conveniently comprise sequences in addition to a polynucleotide ofthe present invention.
  • a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation ofthe polynucleotide.
  • translatable sequences can be inserted to aid in the isolation ofthe translated polynucleotide ofthe present invention.
  • a hexa-histidine marker sequence provides a convenient means to purify the proteins ofthe present invention.
  • the nucleic acid ofthe present invention - excluding the coding sequence - is optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide ofthe present invention.
  • Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation ofthe polynucleotide, or to improve the introduction ofthe polynucleotide into a cell.
  • Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. See, e.g., Ausubel, supra; or Sambrook, supra. Recombinant Methods for Constructing Nucleic Acids
  • RNA, cDNA, genomic DNA, or any combination thereof can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art.
  • oligonucleotide probes that selectively hybridize, under suitable stringency conditions, to the polynucleotides ofthe present invention are used to identify the desired sequence in a cDNA or genomic DNA library.
  • the isolation of RNA, and construction of cDNA and genomic libraries, is well known to those of ordinary skill in the art. (See, e.g., Ausubel, supra; or Sambrook, supra).
  • the isolated nucleic acids ofthe present invention can also be prepared by direct chemical synthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide, which can be converted into double-stranded DNA by hybridization with a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a template.
  • Chemical synthesis of DNA can be limited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences.
  • the present invention further provides recombinant expression cassettes comprising a nucleic acid ofthe present invention.
  • a nucleic acid sequence ofthe present invention for example a cDNA or a genomic sequence encoding a CHI-deleted mimetibody or specified portion or variant ofthe present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell.
  • a recombinant expression cassette will typically comprise a polynucleotide ofthe present invention operably linked to transcriptional initiation regulatory sequences that will direct the transcription ofthe polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be employed to direct expression ofthe nucleic acids ofthe present invention.
  • isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in intron) of a non-heterologous form of a polynucleotide ofthe present invention so as to up or down regulate expression of a polynucleotide of the present invention.
  • endogenous promoters can be altered in vivo or in vitro by mutation, deletion and/or substitution, as known in the art.
  • a polynucleotide ofthe present invention can be expressed in either sense or anti-sense orientation as desired. It will be appreciated that control of gene expression in either sense or anti-sense orientation can have a direct impact on the observable characteristics. Another method of suppression is sense suppression. Introduction of nucleic acid configured in the sense orientation has been shown to be an effective means by which to block the transcription of target genes. Vectors And Host Cells
  • the present invention also relates to vectors that include isolated nucleic acid molecules ofthe present invention, host cells that are genetically engineered with the recombinant vectors, and the production of at least one CHI-deleted mimetibody or specified portion or variant by recombinant techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirely incorporated herein by reference.
  • the polynucleotides can optionally be joined to a vector containing a selectable marker for propagation in a host.
  • a plasmid vector is introduced into a cell using suitable known methods, such as electroporation and the like, other known methods include the use ofthe vector as a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
  • the DNA insert should be operatively linked to an appropriate promoter.
  • the expression constructs will further contain sites optionally for at least one of transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation.
  • the coding portion ofthe mature transcripts expressed by the constructs will preferably include a translation initiating at the beginning and a termination codon (e.g., UAA, UGA or UAG) appropriately positioned at the end ofthe mRNA to be translated, with UAA and UAG preferred for mammalian or eukaryotic cell expression.
  • Expression vectors will preferably but optionally include at least one selectable marker.
  • Such markers include, e.g., but not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US PatNos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, US PatNos. 5,122,464; 5,770,359; 5,827,739) resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria or prokaryotics (the above patents are entirely incorporated hereby by reference).
  • MTX methotrexate
  • DHFR dihydrofolate reductase
  • DHFR dihydrofolate reductase
  • DHFR dihydrofolate reductase
  • DHFR dihydrofolate reduct
  • Suitable vectors will be readily apparent to the skilled artisan.
  • Introduction of a vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18; Ausubel, supra, Chapters 1, 9, 13, 15, 16.
  • At least one CHI-deleted mimetibody or specified portion or variant ofthe present invention can be expressed in a modified form, such as a fusion protein, and can include not only secretion signals, but also additional heterologous functional regions. For instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of a CHI -deleted mimetibody or specified portion or variant to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, peptide moieties can be added to a CHI-deleted mimetibody or specified portion or variant ofthe present invention to facilitate purification. Such regions can be removed prior to final preparation of a CHI -deleted mimetibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.
  • COS-1 e.g., ATCC CRL 1650
  • COS-7 e.g., ATCC CRL-1651
  • HEK293, BHK21 e.g., ATCC CRL-10
  • CHO e.g., ATCC CRL 1610
  • BSC-1 e.g., ATCC CRL-26
  • Preferred host cells include cells of lymphoid origin such as myeloma and lymphoma cells.
  • Particularly preferred host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) and SP2/0-Agl4 cells (ATCC Accession Number CRL-1851).
  • the recombinant cell is a P3X63Ab8.653 or a SP2/0-Agl4 cell.
  • Expression vectors for these cells can include one or more ofthe following expression control sequences, such as, but not limited to an origin of replication; a promoter (e.g., late or early SV40 promoters, the CMV promoter (US PatNos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk
  • phosphoglycerate kinase promoter
  • an EF-1 alpha promoter US Pat.No. 5,266,491
  • at least one human ⁇ nmunoglobulin promoter at least one human ⁇ nmunoglobulin promoter
  • an enhancer, and/or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences.
  • processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences.
  • Other cells useful for production of nucleic acids or proteins ofthe present invention are known and/or available, for instance, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other known or commercial sources.
  • polyadenlyation or transcription terminator sequences are typically incorporated into the vector.
  • An example of a terminator sequence is the polyadenlyation sequence from the bovine growth hormone gene. Sequences for accurate splicing ofthe transcript can also be included.
  • An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)).
  • gene sequences to control replication in the host cell can be incorporated into the vector, as known in the art.
  • a CHI -deleted mimetibody or specified portion or variant can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography.
  • HPLC High performance liquid chromatography
  • Mimetibodies or specified portions or variants ofthe present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells.
  • a eukaryotic host including, for example, yeast, higher plant, insect and mammalian cells.
  • the CHI -deleted mimetibody or specified portion or variant ofthe present invention can be glycosylated or can be non- glycosylated, with glycosylated preferred.
  • the isolated mimetibodies ofthe present invention comprise a CHI-deleted mimetibody or specified portion or variant encoded by any one ofthe polynucleotides ofthe present invention as discussed more fully herein, or any isolated or prepared CHI -deleted mimetibody or specified portion or variant thereof.
  • the CHI -deleted mimetibody or ligand-binding portion or variant binds at least one protein ligand or receptor, and, thereby provides at least one biological activity ofthe corresponding protein or a fragment thereof.
  • Different therapeutically or diagnostically significant proteins are well known in the art and suitable assays or biological activities of such proteins are also well known in the art. The following is a general discussion ofthe variety of proteins, peptides and biological molecules that may be used in the in accordance with the teachings herein. These descriptions do not serve to limit the scope ofthe invention, but rather illustrate the breadth ofthe invention.
  • an embodiment ofthe present invention may target one or more growth factors, or, conversely, derive the target-binding moiety from one or more growth factors.
  • growth factors are hormones or cytokine proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation.
  • Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type.
  • Table 1 presents several factors, but is not intended to be comprehensive or complete, yet introduces some ofthe more commonly known factors and their principal activities.
  • Additional growth factors that may be produced in accordance with the present invention include Activin (Vale et al., 321 Nature 776 (1986); Ling et al, 321 Nature 779 (1986)), Inhibin (U.S. Patent Nos. 4,737,578; 4,740,587), and Bone Morphongenic Proteins (BMPs) (U.S. Patent No. 5,846,931; Wozney, Cellular & Molecular Biology of Bone 131-167 (1993)).
  • Activin Vale et al., 321 Nature 776 (1986); Ling et al, 321 Nature 779 (1986)
  • Inhibin U.S. Patent Nos. 4,737,578; 4,740,587
  • BMPs Bone Morphongenic Proteins
  • the present invention may target or use other cytokines.
  • cytokines Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells.
  • Cytokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines.
  • lymphokines secreted by lymphocytes
  • monocytes or macrophages are termed monokines.
  • a large family of cytokines are produced by various cells ofthe body.
  • Many of the lymphokines are also known as interleukins (TLs), because they are not only secreted by leukocytes, but are also able to affect the cellular responses of leukocytes.
  • TLs interleukins
  • interleukins are growth factors targeted to cells of hematopoietic origin.
  • the list of identified interleukins grows continuously. See, e.g., U.S. Patent No. 6,174,995; U.S. Patent No. 6,143,289; Sallusto et al., 18 Annu. Rev. Immunol. 593 (2000) Kunkel et al., 59 J. Leukocyte Biol. 81 (1996).
  • Additional growth factor/cytokines encompassed in the present invention include pituitary hormones such as human growth hormone (HGH), follicle stimulating hormones (FSH, FSH ⁇ , and FSH ⁇ ), Human Chorionic Gonadotrophins (HCG, HCG ⁇ , HCG ⁇ ), uFSH (urofollitropin), Gonatropin releasing hormone (GRH), Growth Hormone (GH), leuteinizing hormones (LH, LH ⁇ , LH ⁇ ), somatostatin, prolactin, thyrotropin (TSH, TSH ⁇ , TSH ⁇ ), thyrotropin releasing hormone (TRH), parathyroid hormones, estrogens, progesterones, testosterones, or structural or functional analog thereof. All of these proteins and peptides are known in the art.
  • the cytokine family also includes tumor necrosis factors, colony stimulating factors, and interferons. See, e.g., Cosman, 7 Blood Cell (1996); Gruss et al, 85 Blood 3378 (1995); Beutler et al., 7 Annu. Rev. Immunol. 625 (1989); Aggarwal et al., 260 J. Biol. Chem. 2345 (1985); Pennica et al., 312 Nature 724 (1984); R & D Systems, Cytokine Mini-Reviews, at http://www.rndsystems.com. Several cytokines are introduced, briefly, in Table 2 below.
  • cytokines of interest include adhesion molecules (R & D Systems, Adhesion Molecule I (1996), at http://www.rndsystems.com); angiogenin (U.S. Patent No. 4,721,672; Moener et al., 226 Eur. J. Biochem. 483 (1994)); annexin V (Cookson et al., 20 Genomics 463 (1994); Grundmann et al., 85 Proc. Natl. Acad. Sci. USA 3708 (1988); U.S. Patent No. 5,767,247); caspases (U.S. Patent No.
  • MSP Macrophage Stimulating Protein
  • Neurotrophic Factors U.S. Patent Nos. 6,005,081; 5,288,622; Pleiotrophin/Midkine (PTN/MK)
  • cytokines proteins or chemical moieties that interact with cytokines, such as Matrix Metalloproteinases (MMPs) (U.S. Patent No. 6,307,089; Nagase, Matrix Metalloproteinases in Zinc Metalloproteinases in Health and Disease (1996)), and Nitric Oxide
  • the present invention may also be used to affect blood proteins, a generic name for a vast group of proteins generally circulating in blood plasma, and important for regulating coagulation and clot dissolution. See, e.g., Haematologic Technologies, Inc., HTI CATALOG, at www.haemtech.com. Table 3 introduces, in a non-limiting fashion, some ofthe blood proteins contemplated by the present invention.
  • Fibrinogen Plasma fibrinogen a large glycoprotein, FURLAN, Fibrinogen, IN HUMAN disulfide linked dimer made of 3 pairs PROTEIN DATA, (Haeberli, ed, VCH of non-identical chains (Aa, Bb and g), Publishers, N.Y, 1995); Doolittle, in made in liver.
  • Aa has N-terminal peptide HAEMOSTASIS & THROMBOSIS, 491-513 (fibrinopeptide A (FPA), factor XHIa (3rd ed. Bloom et al, eds, Churchill crosslinking sites, and 2 Livingstone, 1994); HANTGAN, et al, in phosphorylation sites.
  • Bb has HAEMOSTASIS & THROMBOSIS 269-89 fibrinopeptide B (FPB), 1 of 3 N-linked (2d ed, Forbes et al, eds, Churchill carbohydrate moieties, and an N- Livingstone, 1991). terminal pyroglutamic acid.
  • the g chain contains the other N-linked glycos. site, and factor XHJa cross-linking sites.
  • Two elongated subunits ((AaBbg) 2 ) align in an antiparallel way forming a trinodular arrangement ofthe 6 chains. Nodes formed by disulfide rings between the 3 parallel chains.
  • Central node n- disulfide knot, E domain
  • Central node n- disulfide knot, E domain
  • Central node n- disulfide knot, E domain
  • Central node n- disulfide knot, E domain
  • Each ofthe 2 domains between the central node and the C-terminal nodes has parallel a- helical regions ofthe Aa, Bb and g chains having protease- (plasmin-) sensitive sites.
  • Another major plasmin sensitive site is in hydrophilic preturbance of a-chain from C-terminal node. Controlled plasmin degradation converts Fbg into fragments D and E.
  • Additional blood proteins contemplated herein include the following human serum proteins, which may also be placed in another category of protein (such as hormone or antigen): Actin, Actinin, Amyloid Serum P, Apolipoprotein E, B2-Microglobulin, C-Reactive Protein (CRP), Cholesterylester transfer protein (CETP), Complement C3B, Ceruplasmin, Creatine Kinase, Cystatin, Cytokeratin 8, Cytokeratin 14, Cytokeratin 18, Cytokeratin 19, Cytokeratin 20, Desmin, Desmocollin 3, FAS (CD95), Fatty Acid Binding Protein, Ferritin, Filamin, Glial Filament Acidic Protein, Glycogen Phosphorylase Isoenzyme BB (GPBB), Haptoglobulin, Human Myoglobin, Myelin Basic Protein, Neurofilament, Placental Lactogen, Human SHBG, Human Thyroid Peroxidase, Receptor Associated Protein, Human
  • the target in the present invention may also incorporate or target neurotransmitters, or functional portions thereof.
  • Neurotransmitters are chemicals made by neurons and used by them to transmit signals to the other neurons or non-neuronal cells (e.g, skeletal muscle; myocardium, pineal glandular cells) that they innervate.
  • Neurotransmitters produce their effects by being released into synapses when their neuron of origin fires (i.e., becomes depolarized) and then attaching to receptors in the membrane ofthe post-synaptic cells. This causes changes in the fluxes of particular ions across that membrane, making cells more likely to become depolarized, if the neurotransmitter happens to be excitatory, or less likely if it is inhibitory.
  • Neurotransmitters can also produce their effects by modulating the production of other signal-transducing molecules ("second messengers") in the post- synaptic cells. See generally COOPER, BLOOM & ROTH, THE BIOCHEMICAL BASIS OF NEUROPHARMACOLOGY (7th Ed. Oxford Univ. Press, NYC, 1996); http://web.indstate.edu/thcme/mwking/nerves.
  • Neurotransmitters contemplated in the present invention include, but are not limited to, Acetylcholine, Serotonin, ⁇ -aminobutyrate (GABA), Glutamate, Aspartate, Glycine, Histamine, Epinephrine, Norepinephrine, Dopamine, Adenosine, ATP, Nitric oxide, and any ofthe peptide neurotransmitters such as those derived from pre-opiomelanocortin (POMC), as well as antagonists and agonists of any ofthe foregoing.
  • GABA ⁇ -aminobutyrate
  • Aspartate Glycine
  • Histamine Histamine
  • Epinephrine Epinephrine
  • Norepinephrine Norepinephrine
  • Dopamine Adenosine
  • ATP Nitric oxide
  • any ofthe peptide neurotransmitters such as those derived from pre-opiomelanocortin (POMC), as well as antagonists and agonists of any
  • peptides may be used in conjunction with the present invention.
  • peptides that mimic the activity of EPO, TPO, growth hormone, G-CSF, GM-CSF, IL-lra, leptin, CTLA4, TRAIL, TGF- ⁇ , and TGF- ⁇ .
  • Peptide antagonists are also of interest, particularly those antagonistic to the activity of TNF, leptin, any ofthe interleukins (TL-1 - IL-23, etc.), and proteins involved in complement activation (e.g, C3b).
  • Targeting peptides are also of interest, including tumor-homing peptides, membrane-transporting peptides, and the like. All of these classes of peptides may be discovered by methods described in the references cited in this specification and other references.
  • a particularly preferred group of peptides are those that bind to cytokine receptors. Cytokines have recently been classified according to their receptor code. See Inglot (1 97), Archivum Immunologiae e Therapiae Experimentalis 45: 353-7, which is hereby incorporated entirely by reference.
  • Non-limiting examples of suitable peptides for this invention appear in Tables 5 through 21 below. These peptides may be prepared by methods disclosed and/or known in the art. Single letter amino acid abbreviations are used in most cases.
  • the X in these sequences (and throughout this specification, unless specified otherwise in a particular instance) means that any ofthe 20 naturally occurring amino acid residues or know derivatives thereof may be present, or any know modified amino acid thereof. Any of these peptides may be linked in tandem (i.e., sequentially), with or without linkers, and a few tandemlinked examples are provided in the table. Linkers are listed as " ⁇ " and may be any ofthe linkers described herein.
  • Tandem repeats and linkers are shown separated by dashes for clarity.
  • Any peptide containing a cysteinyl residue may optionally be cross-linked with another Cys-containing peptide, either or both of which may be linked to a vehicle.
  • a few crosslinked examples are provided in the table.
  • Any peptide having more than one Cys residue may form an intrapeptide disulfide bond, as well; see, for example, EPO-mimetic peptides in Table 5.
  • intrapeptide disulfide-bonded peptides are specified in the table. Any of these peptides may be derivatized as described herein, and a few derivatized examples are provided in the table.
  • the capping amino group is shown as -NH 2 .
  • amino acid residues are substituted by moieties other than amino acid residues
  • the substitutions are denoted by a ⁇ , which signifies any ofthe moieties known in the art, e.g, as described in Bhatnagar et al. (1996), J. Med. Chem. 39: 3814-9 and Cuthbertson et al. (1997), J. Med. Chem. 40:2876-82, which are entirely incorporated by reference.
  • the J substituent and the Z substituents (Z 5 , Zg, ... Z 40 ) are as defined in U.S. Pat. Nos.
  • Xaa and Yaa below are as defined in WO 98/09985, published March 12,1998, which is entirely incorporated herein by reference.
  • AAj, AA 2 , ABi, AB 2 , and AC are as defined in International application WO 98/53842, published December 3, 1998, which is entirely incorporated by reference.
  • X 1 , X 2 , X 3 , and X 4 in Table 18 only are as, defined in European application EP 0 911 393, published April 28,1999, entirely incorporated herein by reference.
  • Residues appearing in boldface are D-amino acids, but can be optionally L-amino acids. All peptides are linked through peptide bonds unless otherwise noted. Abbreviations are listed at the end of this specification. In the "SEQ ID NO.” column, "NR" means that no sequence listing is required for the given sequence.
  • FEWTPGWWQPY 69 FEWTPNYWQPY 70 FEVffPvYWQJY 71 FEWTPecGYWQJY 72 FEWTPAibYWQJY 73 FEVffSarGYWQJY 74 FEWTPGYWQPY 75 FEWTPGYWQHY 76 FEWTPGWYQJY 77 AcFEWTPGWYQJY 78 FEWTPGW-pY-QJY 79 FAWTPGYWQJY 80 FEWAPGYWQJY 81 FEWVPGYWQJY 82 FEWTPGYWQJY 83 AcFEWTPGYWQJY 84 FEWTPAWYQJY 85 FEWTPSarWYQJY 86 FEWTPGYYQPY 87 FEWTPGWWQPY FEWTPNYWQPY 89 FEWTPVYWQJ
  • TKPR 100 RKSSK 101 RKQDK 102 NRKQDK 103 RKQDKR 104 — . ⁇ i iv w 105
  • VGRWYQPYSVQR 143 VHVYWQPYSVQR 144
  • SDAFTTQDSQAMYWQPYALPL 309 GDDAAWRTDSLTYWQPYALPL 310
  • ETPFTWEESNAWAIQPYALPL 354 ENTYSPNWADSMYWQPYALPL 355
  • VYWQPYSVQ 394 VY-Nap-QPYSVQ 395
  • AENWADNEPNNKRNNED 600 RKNNKTWTWVGTKKALTNE 601 KKALTNEAENWAD 602
  • RIIVKIRLRI ⁇ KKTRL 666 KIGIKARVR ⁇ RVK ⁇ 667
  • RIWHIRLRriHHIRL 668 fflGIKAHVR ⁇ RVH ⁇ 669
  • KPfflKARPTHRYKMI 686 cyclicCKGFFALIPKHSSPLFKTLLSAVC 687
  • SWDEKGLWSA 775 SWDSSGLWMD 776
  • the present invention is also particularly useful with peptides having activity in treatment of: a VEGF related condition, e.g., but not limited to, cancer, wherein the peptide is a VEGF-mimetic or a VEGF receptor antagonist, a HER2 agonist or antagonist, a CD20 antagonist and the like; asthma, wherein the protein of interest is a CKR3 antagonist, an IL-5 receptor antagonist, and the like; thrombosis, wherein the protein of interest is a GP ⁇ b antagonist, a GPHIa antagonist, and the like; autoimmune diseases and other conditions involving immune modulation, wherein the protein of interest is an IL-2 receptor antagonist, a CD40 agonist or antagonist, a CD40L agonist or antagonist, a thymopoietin mimetic and the like.
  • a VEGF related condition e.g., but not limited to, cancer
  • the peptide is a VEGF-mimetic or a VEGF receptor antagonist
  • EPO biological activities are well known in the art. See, e.g., Anagnostou A et al Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proceedings ofthe National Academy of Science (USA) 87: 5978-82 (1990); Fandrey J and Jelkman WE Interleukin 1 and tumor necrosis factor-alpha inhibit erythropoietin production in vitro. Annals ofthe New York Academy of Science 628: 250-5 (1991); Geissler K et al Recombinant human erythropoietin: A multipotential hemopoietic growth factor in vivo and in vitro. Contrib. Nephrol.
  • EPO can be assayed by employing cell lines such as HCD57 , NFS-60 , TF-1 and UT-7 , which respond to the factor . EPO activity can be assessed also in a Colony formation assay by determining the number of CFU-E from bone marrow cells.
  • An alternative and entirely different detection method is RT-PCR quantitation of cytokines.
  • a CHI -deleted mimetibody, or specified portion or variant thereof, that partially or preferably substantially provides at least one biological activity of at least one protein or fragment, can bind the protein or fragment ligand and thereby provide at least one activity that is otherwise mediated through the binding of protein to at least one protein ligand or receptor or through other protein-dependent or mediated mechanisms.
  • CHI-deleted mimetibody activity refers to a CHI- deleted mimetibody that can modulate or cause at least one protein-dependent activity by about 20- 10,000%, preferably by at least about 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 % or more depending on the assay.
  • CHI -deleted mimetibody or specified portion or variant to provide at least one protein-dependent activity is preferably assessed by at least one suitable protein biological assay, as described herein and/or as known in the art.
  • a human CHI-deleted mimetibody or specified portion or variant ofthe invention can be similar to any class (IgG, IgA, IgM, etc.) or isotype and can comprise at least a portion of a kappa or lambda light chain, wherein at least one ofthe LBRs is replaced by at least one LBR as described herein.
  • the human CHI -deleted mimetibody or specified portion or variant comprises an IgG heavy chain or defined fragment, for example, at least one of isotypes, IgGl, IgG2, IgG3 or IgG4.
  • the human protein human CHI- deleted mimetibody or specified portion or variant thereof comprises an IgGl heavy chain and an IgGl light chain.
  • At least one CHI -deleted mimetibody or specified portion or variant ofthe invention binds at least one specified ligand specific to at least one protein, subunit, fragment, portion or any combination thereof.
  • the at least one LBR of at least one CHI -deleted mimetibody, specified portion or variant ofthe present invention can optionally bind at least one specified ligand epitope ofthe ligand.
  • the binding epitope can comprise any combination of at least one amino acid sequence of at least 1-3 amino acids to the entire specified portion of contiguous amino acids ofthe sequences selected from the group consisting of a protein ligand, such as a receptor or portion thereof.
  • the CHI -deleted mimetibody or ligand-binding fragment ofthe present invention can comprise a ligand binding region (LBR) (e.g., LBR1, LBR2 and LBR3) or variant provided in at least one heavy chain variable region and at least one ligand binding region (LBR1, LBR2 and LBR3) or variant provided in at least one light chain variable region.
  • LBR ligand binding region
  • the CH1- deleted mimetibody or ligand-binding portion or variant can comprise at least one ofthe heavy chain LBR3, and/or a light chain LBR3.
  • the CHI -deleted mimetibody or ligand- binding fragment can have an ligand-binding region that comprises at least a portion of at least one heavy chain LBR (i.e., LBR1, LBR2 and/or LBR3) having the amino acid sequence ofthe corresponding LBRs 1, 2 and/or 3.
  • the CHI -deleted mimetibody or ligand-binding portion or variant can have an ligand-binding region that comprises at least a portion of at least one light chain LBR (i.e., LBR1, LBR2 and/or LBR3) having the amino acid sequence ofthe corresponding LBRs 1, 2 and/or 3.
  • Such mimetibodies can be prepared by joining together the various portions (e.g., LBRs, framework) ofthe CHI-deleted mimetibody using known techniques, by preparing and expressing at least one (i.e., one or more) nucleic acid molecules that encode the CH1- deleted mimetibody, using known techniques of recombinant DNA technology or by using any other suitable method, such as chemical synthesis.
  • the CHI -deleted mimetibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence.
  • Mimetibodies that bind to human protein ligands or receptors and that comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as phage display (Katsube, Y., et al, Int J Mol. Med, l(5):863-868 (1998)) or methods that employ transgenic animals, as known in the art and/or as described herein.
  • the CHI- deleted mimetibody, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable host cell.
  • the invention also relates to mimetibodies, ligand-binding fragments, immunoglobulin chains and LBRs comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein.
  • mimetibodies or ligand-binding fragments and mimetibodies comprising such chains or LBRs can bind human protein ligands with high affinity (e.g., K D less than or equal to about 10 "9 M).
  • Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions.
  • a conservative amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/ hydrophilicity) that are similar to those ofthe first amino acid.
  • Conservative substitutions include replacement of one amino acid by another within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T.
  • amino acids that make up mimetibodies or specified portions or variants ofthe present invention are often abbreviated.
  • the amino acid designations can be indicated by designating the amino acid by its single letter code, its three letter code, name, or three nucleotide codon(s) as is well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994):
  • a CHI -deleted mimetibody or specified portion or variant ofthe present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation, as specified herein.
  • the number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above.
  • the number of amino acid substitutions, insertions or deletions for at least one of a CHI -deleted mimetibody LBR, variable, constant, light or heavy chain, or Ig will not be more than 40, 30, 20,19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 amino acids, such as 1-30 or any range or value therein, as specified herein.
  • Amino acids in a CHI -deleted mimetibody or specified portion or variant ofthe present invention that are essential for function can be identified by methods known in the art, such as site- directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)).
  • site- directed mutagenesis or alanine-scanning mutagenesis e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)
  • the latter procedure introduces single alanine mutations at every residue in the molecule.
  • the resulting mutant molecules are then tested for biological activity, such as, but not limited to at least one protein related activity, as specified herein or as known in the art.
  • Sites that are critical for CHI -deleted mimetibody or specified portion or variant binding can also be identified by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).
  • Mimetibodies or specified portions or variants ofthe present invention can comprise as the Pep portion of Formula (I), but are not limited to, at least one portion, sequence or combination selected from 3 to all the of at least one of SEQ ID NOS: 1-979.
  • Non-limiting variants that can enhance or maintain at least one ofthe listed activities include, but are not limited to, any ofthe above polypeptides, further comprising at least one mutation corresponding to at least one substitution, insertion or deletion that does not significantly affect the suitable biological activtities or functions of said CHI -deleted mimetibody.
  • a CHI -deleted mimetibody or specified portion or variant can further optionally comprise at least one functional portion of at least one polypeptide as Pep portion of Formula (I), at least one of 90- 100% of SEQID NOS:l-l 109.
  • a CHI-deleted mimetibody can further optionally comprise an amino acid sequence for the Pep portion of Formula (I), selected from one or more of SEQID NOS:l-l 109.
  • the Pep amino acid sequence of an immunoglobulin chain, or portion thereof has about 90-100% identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the corresponding amino acid sequence ofthe corresponding portion of at least one of SEQ ID NOS: 1-979.
  • 90- 100% amino acid identity i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein
  • 90- 100% amino acid identity is determined using a suitable computer algorithm, as known in the art.
  • Mimetibodies or specified portions or variants ofthe present invention can comprise any number of contiguous amino acid residues from a CHI-deleted mimetibody or specified portion or variant ofthe present invention, wherein that number is selected from the group of integers consisting of from 10-100% ofthe number of contiguous residues in a CHI-deleted mimetibody.
  • this subsequence of contiguous amino acids is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,
  • the present invention includes at least one biologically active CHI-deleted mimetibody or specified portion or variant ofthe present invention.
  • Bioly active mimetibodies or specified portions or variants have a specific activity at least 20%, 30%, or 40%, and preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95%-1000% of that of the native (non-synthetic), endogenous or related and known inserted or fused protein or specified portion or variant.
  • Methods of assaying and quantifying measures of enzymatic activity and substrate specificity are well known to those of skill in the art.
  • the invention relates to human mimetibodies and ligand-binding fragments, as described herein, which are modified by the covalent attachment of an organic moiety.
  • modification can produce a CHI -deleted mimetibody or ligand-binding fragment with improved pharmacokinetic properties (e.g., increased in vivo serum half-life).
  • the organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group.
  • the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, and the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.
  • a polyalkane glycol e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)
  • carbohydrate polymer e.g., amino acid polymer or polyvinyl pyrolidone
  • the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.
  • the modified mimetibodies and ligand-binding fragments ofthe invention can comprise one or more organic moieties that are covalently bonded, directly or indirectly, to the CHI -deleted mimetibody or specified portion or variant.
  • Each organic moiety that is bonded to a CHI-deleted mimetibody or ligand-binding fragment ofthe invention can independently be a hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
  • fatty acid encompasses mono-carboxylic acids and di-carboxylic acids.
  • Hydrophilic polymers suitable for modifying mimetibodies ofthe invention can be linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone.
  • polyalkane glycols e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like
  • carbohydrates e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like
  • polymers of hydrophilic amino acids e.g., poly
  • the hydrophilic polymer that modifies the CHI -deleted mimetibody ofthe invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity.
  • PEG2 5 oo > PEG 50 oo, PEG 75 oo, PEGgooo, PEG] oooo, PEG ⁇ 25 oo, PEG ⁇ 500 o, and PEG 2 o,ooo, wherein the subscript is the average molecular weight ofthe polymer in Daltons can be used.
  • the hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups.
  • Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods.
  • a polymer comprising an amine group can be coupled to a carboxylate ofthe fatty acid or fatty acid ester, and an activated carboxylate (e.g., activated with N,N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hydroxyl group on a polymer.
  • an activated carboxylate e.g., activated with N,N-carbonyl diimidazole
  • Fatty acids and fatty acid esters suitable for modifying mimetibodies ofthe invention can be saturated or can contain one or more units of unsaturation.
  • Fatty acids that are suitable for modifying mimetibodies ofthe invention include, for example, n-dodecanoate (Cn, laurate), n-tetradecanoate (Cj 4 , myristate), n-octadecanoate (C ⁇ 8 , stearate), n-eicosanoate (C 2 o, arachidate), n-docosanoate (C 22 , behenate), n-triacontanoate (C 3 0), n-tetracontanoate (C 40 ), cw- ⁇ 9-octadecanoate (C 18 , oleate), all cis- 5,8,11,14-eicosatetraenoate (C 2 0, arachidonate), octanedioic acid, t
  • Suitable fatty acid esters include mono-esters of dicarboxylic acids that comprise a linear or branched lower alkyl group.
  • the lower alkyl group can comprise from one to about twelve, preferably one to about six, carbon atoms.
  • the modified human mimetibodies and ligand-binding fragments can be prepared using suitable methods, such as by reaction with one or more modifying agents.
  • activating group is a chemical moiety or functional group that can, under appropriate conditions, react with a second chemical group thereby forming a covalent bond between the modifying agent and the second chemical group.
  • amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like.
  • Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol-2- nitrobenzoic acid thiol (TNB-thiol), and the like.
  • An aldehyde functional group can be coupled to amine- or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorous group to form phosphoramidate or phosphorimide linkages.
  • Suitable methods to introduce activating groups into molecules are known in the art (see for example, Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)).
  • An activating group can be bonded directly to the organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or through a linker moiety, for example a divalent C 1 -C 12 group wherein one or more carbon atoms can be replaced by a heteroatom such as oxygen, nitrogen or sulfur.
  • Suitable linker moieties include, for example, tetraethylene glycol, -(CH 2 ) -, -NH-(CH 2 ) 6 -NH-, -(CH 2 ) 2 -NH- and -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH2-O-CH-NH-.
  • Modifying agents that comprise a linker moiety can be produced, for example, by reacting a mono-Boc- alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate.
  • a mono-Boc- alkyldiamine e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • the Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimido derivative ofthe fatty acid.
  • TFA trifluoroacetic acid
  • the modified mimetibodies ofthe invention can be produced by reacting an human CH1- deleted mimetibody or ligand-binding fragment with a modifying agent.
  • a modifying agent for example, the organic moieties can be bonded to the CHI -deleted mimetibody in a non-site specific manner by employing an amine-reactive modifying agent, for example, an NHS ester of PEG.
  • Modified human mimetibodies or ligand-binding fragments can also be prepared by reducing disulfide bonds (e.g., intra-chain disulfide bonds) of a CHI -deleted mimetibody or ligand-binding fragment.
  • the reduced CHI -deleted mimetibody or ligand-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified CHI -deleted mimetibody ofthe invention.
  • Modified human mimetibodies and ligand-binding fragments comprising an organic moiety that is bonded to specific sites of a CH1- deleted mimetibody or specified portion or variant ofthe present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al, Bioconjugate Chem., 3:147-153 (1992); Werlen et al, Bioconjugate Chem., 5:411-417 (1994); Kumaran et al, Protein Sci.
  • the present invention also provides at least one CHI -deleted mimetibody or specified portion or variant composition
  • at least one CHI -deleted mimetibody or specified portion or variant composition comprising at least one, at least two, at least three, at least four, at least five, at least six or more mimetibodies or specified portions or variants thereof, as described herein and/or as known in the art that are provided in a non-naturally occurring composition, mixture or form.
  • Such composition percentages are by weight, volume, concentration, molarity, or molality as liquid or dry solutions, mixtures, suspension, emulsions or colloids, as known in the art or as described herein.
  • compositions can comprise 0.00001-99.9999 percent by weight, volume, concentration, molarity, or molality as liquid, gas, or dry solutions, mixtures, suspension, emulsions or colloids, as known in the art or as described herein, on any range or value therein, such as but not limited to 0.00001, 0.00003, 0.00005, 0.00009, 0.0001, 0.0003, 0.0005, 0.0009, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.1, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.1, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.1, 3.8, 3.9, 4.0, 4.3, 4.5
  • composition can optionally further comprise an effective amount of at least one compound or protein selected from at least one of an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplactic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like.
  • CV cardiovascular
  • CNS central nervous system
  • ANS autonomic nervous system
  • GI gastrointestinal
  • a hormonal drug a drug for fluid or electrolyte balance
  • hematologic drug an antineoplactic
  • an immunomodulation drug an ophthalmic, otic or nasal drug
  • topical drug a nutritional drug or the like.
  • Such drugs are well known in the art, including formulations, indications, dosing and administration for each presented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21 st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ; Pharmcotherapy Handbook, Wells et al., ed., Appleton & Lange, Stamford, CT, each entirely incorporated herein by reference).
  • the anti-infective drug can be at least one selected from amebicides or at least one antiprotozoals, anthelmintics, antifungals, antimalarials, antituberculotics or at least one antileprotics, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infectives, miscellaneous anti-infectives.
  • the CV drug can be at least one selected from inotropics, antiarrhythmics, antianginals, antihypertensives, antilipemics, and miscellaneous cardiovascular drugs.

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Abstract

La présente invention concerne au moins un nouveau corps mimétique humain à délétion CH1 ou une partie spécifiée ou un variant de ce corps, et notamment des acides nucléiques isolés qui codent au moins un corps mimétique à délétion CH1 ou une partie spécifiée ou un variant de celui-ci, un corps mimétique à délétion CH1 ou une partie spécifiée ou des variants, vecteurs, cellules hôtes, animaux transgéniques ou plantes, ainsi que des procédés de fabrication et d'utilisation de corps mimétiques. L'invention se rapporte notamment à des compositions thérapeutiques, à des procédés et à des dispositifs associés.
EP03742272A 2002-06-28 2003-06-27 Corps mimetiques mammaliens a deletion ch1, compositions, procedes et utilisations Withdrawn EP1545608A4 (fr)

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US6660843B1 (en) 1998-10-23 2003-12-09 Amgen Inc. Modified peptides as therapeutic agents
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EP1545608A4 (fr) 2006-09-13
WO2004002417A2 (fr) 2004-01-08
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