WO2006107617A2 - Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses - Google Patents

Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses Download PDF

Info

Publication number
WO2006107617A2
WO2006107617A2 PCT/US2006/010762 US2006010762W WO2006107617A2 WO 2006107617 A2 WO2006107617 A2 WO 2006107617A2 US 2006010762 W US2006010762 W US 2006010762W WO 2006107617 A2 WO2006107617 A2 WO 2006107617A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
precursor
antigen
virus
antibody
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.)
Ceased
Application number
PCT/US2006/010762
Other languages
English (en)
French (fr)
Other versions
WO2006107617A3 (en
Inventor
Hsing Chang Chien
David M. Goldenberg
William J. Mcbride
Edmund A. Rossi
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.)
IBC Pharmaceuticals Inc
Original Assignee
IBC Pharmaceuticals 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 IBC Pharmaceuticals Inc filed Critical IBC Pharmaceuticals Inc
Priority to AU2006232920A priority Critical patent/AU2006232920B2/en
Priority to EP06748646A priority patent/EP1874824A4/en
Priority to CA2604032A priority patent/CA2604032C/en
Priority to CN200680019840.6A priority patent/CN101484182B/zh
Priority to JP2008505356A priority patent/JP5011277B2/ja
Priority to CA2607056A priority patent/CA2607056C/en
Priority to PCT/US2006/025499 priority patent/WO2007046893A2/en
Priority to AU2006302848A priority patent/AU2006302848C1/en
Priority to JP2008536564A priority patent/JP5231231B2/ja
Priority to EP06785922A priority patent/EP1937851A4/en
Priority to US11/478,021 priority patent/US7534866B2/en
Publication of WO2006107617A2 publication Critical patent/WO2006107617A2/en
Priority to AU2006330051A priority patent/AU2006330051B2/en
Priority to CN201610087781.1A priority patent/CN105709237A/zh
Priority to SG200904095-7A priority patent/SG153825A1/en
Priority to US11/633,729 priority patent/US7527787B2/en
Priority to EP06848816.2A priority patent/EP1959993B1/en
Priority to CA2633486A priority patent/CA2633486C/en
Priority to CN200680052809.2A priority patent/CN101374546B/zh
Priority to JP2008545643A priority patent/JP5090366B2/ja
Priority to PCT/US2006/046367 priority patent/WO2007075270A2/en
Priority to EP13004490.2A priority patent/EP2674440B1/en
Priority to KR1020087017349A priority patent/KR101410521B1/ko
Priority to HK08110462.0A priority patent/HK1117761B/en
Priority to CN201310087033.XA priority patent/CN103242451B/zh
Anticipated expiration legal-status Critical
Priority to US11/925,408 priority patent/US7666400B2/en
Publication of WO2006107617A3 publication Critical patent/WO2006107617A3/en
Priority to US12/396,605 priority patent/US7858070B2/en
Priority to US12/417,917 priority patent/US7906121B2/en
Priority to US12/644,146 priority patent/US7981398B2/en
Priority to US12/731,781 priority patent/US8003111B2/en
Priority to US12/766,092 priority patent/US8067006B2/en
Priority to US12/871,345 priority patent/US8551480B2/en
Priority to US12/949,536 priority patent/US8211440B2/en
Priority to US13/021,302 priority patent/US8246960B2/en
Priority to US13/150,613 priority patent/US8277817B2/en
Priority to US13/178,092 priority patent/US8158129B2/en
Priority to US13/246,389 priority patent/US8338140B2/en
Priority to US13/412,816 priority patent/US8435540B2/en
Priority to US13/483,761 priority patent/US20120276608A1/en
Priority to US13/549,906 priority patent/US8865176B2/en
Priority to US13/589,575 priority patent/US9457100B2/en
Priority to US13/670,790 priority patent/US8889835B2/en
Priority to US13/688,812 priority patent/US8883162B2/en
Priority to US13/710,908 priority patent/US8652484B2/en
Priority to US13/851,404 priority patent/US20130217091A1/en
Priority to US14/017,885 priority patent/US9481878B2/en
Priority to US14/488,921 priority patent/US9169470B2/en
Priority to US14/505,595 priority patent/US9862770B2/en
Priority to US14/510,746 priority patent/US9707300B2/en
Priority to US14/598,664 priority patent/US9441043B2/en
Priority to US14/854,873 priority patent/US20150374846A1/en
Priority to US15/224,882 priority patent/US9751948B2/en
Priority to US15/247,386 priority patent/US9872920B2/en
Priority to US15/264,747 priority patent/US20160375108A1/en
Priority to US15/646,813 priority patent/US10377829B2/en
Priority to US15/827,637 priority patent/US20180079816A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6853—Carcino-embryonic antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1048—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell determinant being a carcino embryonic antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction

Definitions

  • problems may include high manufacturing cost, low expression yields, instability in serum, instability in solution resulting in formation of aggregates or dissociated subunits, undefined batch composition due to the presence of multiple product forms, contaminating side-products, reduced functional activities or binding affinity/avidity attributed to steric factors or altered conformations, etc.
  • high manufacturing cost and heterogeneity of the purified product are two major limitations.
  • the present invention discloses a platform technology for generating stably tethered structures that may have multiple functions or binding specificities or both, and are suitable for in vitro as well as in vivo applications.
  • the stably tethered structures are produced as a homodimer of any organic substance, which can be proteins or nonproteins.
  • the homodimer referred to as a 2 hereafter, is composed of two identical subunits linked to each other via a distinct peptide sequence, termed the dimerization and docking domain (DDD), which is contained in each subunit.
  • DDD dimerization and docking domain
  • the subunit is constructed by linking a DDD sequence to a precursor of interest by recombinant engineering or chemical conjugation via a spacer group, resulting in a structure that is capable of self-association to form a dimer.
  • Representative 32 constructs made with the DDD sequence referred to as DDDl are described in Examples 2 and 3.
  • the stably tethered structures are produced predominantly as a homotetramer of any organic substance, which can be proteins or non-proteins.
  • the homotetramer referred to as a_j hereafter, is composed of two identical 3 2 constructs made with the DDD sequence referred to as DDD2 ( Figure Ib, SEQ ID NO:2), which is contained in each of the four subunits. Five such 8 4 constructs are described in Examples 4 and 5.
  • the stably tethered structures are produced as a hybrid tetramer from any two distinct 3 4 constructs.
  • the hybrid tetramer referred to as 82a'2 hereafter, is composed of two different a 2 constructs derived from respective 84 constructs. Three such 3 2 a 5 2 constructs are described in Example 6. hi other embodiments, fusion proteins that are single-chain polypeptides comprising multiple domains, such as avimers (Silverman et al., Nat. Biotechnol. (2005), 23: 1556-1561) for example, may serve as precursors of interest to increase the valency, functionality, and specificity of the resulting a2, 3 4 and 3 2 a 5 2 constructs, which may be further conjugated with effectors and carriers to acquire additional functions enabled by such modifications.
  • Type 1 A bivalent 3 2 construct composed of two Fab or scFv fragments derived from the same mAb. See Table 1 for selected examples.
  • Type 2 A bivalent 3 2 construct composed of two identical non-immunoglobulin proteins. See Table 2 for selected examples.
  • Type 3 A tetravalent 3 4 construct composed of four Fab or scFv fragments derived from the same mAb. See Table 3 for selected examples.
  • Type 4 A tetravalent 3 4 constructs composed of four identical non-immunoglobulin proteins. See Table 4 for selected examples.
  • Type 5 A bispecific tetravalent 3 2 8* 2 construct composed of two Fab or scFv fragments derived from the same mAb and two Fab or scFv fragment derived from a different mAb. See Table 5 for selected examples.
  • Type 6 A multifunctional aj&'i constructs composed of two Fab or scFv fragments derived from the same mAb and two identical non-immunoglobulin proteins. See Table 6 for selected examples.
  • Type 7 A multifunctional a2a' 2 constructs composed of two pairs of different non- immunoglobulin proteins. See Table 7 for selected examples.
  • the products in the type 1 category are useful in various applications where a bivalent binding protein composed of two stably tethered Fab (or scFv) fragments derived from the same monoclonal antibody is more desirable than the corresponding bivalent F(ab')2, which is known to dissociate into monovalent Fab' in vivo.
  • a bivalent binding protein composed of two stably tethered Fab (or scFv) fragments derived from the same monoclonal antibody is more desirable than the corresponding bivalent F(ab')2, which is known to dissociate into monovalent Fab' in vivo.
  • the efficacy of an a2 product composed of two stably tethered Fab fragments of 7E3 should be improved over that of ReoProTM (Centocor, Inc.), which uses the Fab fragment of 7E3 to prevent platelet aggregation.
  • the products in the type 2 category are useful in various applications where a bivalent agent may be more desirable than a monovalent agent either for improved efficacy or pharmacokinetics or both.
  • a bivalent agent may be more desirable than a monovalent agent either for improved efficacy or pharmacokinetics or both.
  • an a 2 product composed of two copies of erythropoietin may be preferred to Epogen® (Amgen), which contains only one erythropoietin.
  • Epogen® Amgen
  • Another example is an a ⁇ product composed of two copies of A ⁇ l2-28P fused to the CH2 and CH3 domains of human IgGl.
  • a ⁇ l2-28P is the peptide containing the N- terminal 12 to 28 residues of ⁇ -amyloid (A ⁇ ) with valine at position 18 replaced by proline.
  • a ⁇ l2-28P is non-fibrillogenic and nontoxic and can block the binding of apolipoprotein E (apoE) to A ⁇ with reduction of A ⁇ plaques in a transgenic mouse model (Sadowski et al., Am J Pathol. (2004), 165: 937-948).
  • the fusion of CH2 and CH3 to A ⁇ l2-28P would serve two purposes: (1) to facilitate the resulting complex to cross the blood brain barrier through the FcRn; (2) for effective reduction of A ⁇ plaque by microglia cells following binding of A ⁇ to the anti-A ⁇ arms and binding of the CH2-CH3 domain to the Fc receptors on microglia (Hartman et al., J. Neurosci. (2005), 25: 6213-6220).
  • the products in the type 3 category are useful in various applications where a tetravalent binding protein composed of four stably tethered Fab (or scFv) fragments derived from the same monoclonal antibody is more desirable than a trivalent, bivalent or monovalent binding protein based on the same monoclonal antibody.
  • a tetravalent binding protein composed of four stably tethered Fab (or scFv) fragments derived from the same monoclonal antibody is more desirable than a trivalent, bivalent or monovalent binding protein based on the same monoclonal antibody.
  • the efficacy of an 3 4 product composed of four stably tethered Fab fragments of an anti-TNF- ⁇ antibody such as adalimumab may be more efficacious in treating arthritis than HUMIRATM (Abbott Laboratories).
  • the products in the type 4 category are useful in various applications where a tetravalent agent may be more desirable than a trivalent, bivalent or monovalent agent due to the enhanced avidity of binding to the target.
  • a tetravalent agent may be more desirable than a trivalent, bivalent or monovalent agent due to the enhanced avidity of binding to the target.
  • an a 4 product composed of four copies of factor IX may be preferred as a therapeutic agent for treating hemophilia to BenefixTM (Wyeth), which contains only one factor IX.
  • the products in the type 5 category are useful in various applications where a bispecific tetravalent binding protein composed of two different & 2 subunits is desired.
  • an a 2 a s 2 product composed of two Fab fragments of trastuzumab and two Fab fragments of pertuzumab maybe more efficacious than either Herceptin® (Genentech) or OmnitargTM (Genentech) for treating cancers that overexpress the HER2 receptor.
  • the products in the type 6 category are useful in various applications where target-specific delivery or binding of a non-immunoglobulin protein is desired.
  • a ⁇ a' ⁇ product composed of two Fab fragments of an internalizing antibody against a tumor associated antigen (such as CD74) and two copies of a toxin (such as deglycosylated ricin A chain or ranpirnase) would be valuable for selective delivery of the toxin to destroy the target tumor cell.
  • a 2 a 5 2 product composed of two Fab fragments of an antibody against A ⁇ and two copies of transferin (Tf), which is expected to cross the blood brain barrier and neutralize A ⁇ for effective therapy of Alzheimer's disease.
  • the products in the type 7 category are useful in various applications where the combination of two different non-immunoglobulin proteins are more desirable than each respective non-immunoglobulin protein alone.
  • an a23 5 2 product composed of two copies of a soluble component of the receptor for IL-4R (sIL-4R) and two copies of a soluble component of the receptor for IL- 13 (sIL-13R) would be a potential therapeutic agent for treating asthma or allergy.
  • Another example is an a 2 a J 2 product composed of two copies of A ⁇ l2-28P and two copies of Tf. The addition of Tf to A ⁇ l2-28P is expected to enable the resulting complex to cross the blood brain barrier for effective treatment of Alzheimer's disease.
  • the stably tethered structures of the present invention are suitable for use in a wide variety of therapeutic and diagnostic applications.
  • the a 2) 3 4 , or a 2 a' 2 constructs based on the antibody binding domains can be used for therapy where such a construct is not conjugated to an additional functional agent, in the same manner as therapy using a naked antibody.
  • these stably tethered structures can be derivatized with one or more functional agents to enable diagnostic or therapeutic applications.
  • the additional agent may be covalently linked to the stably tethered structures using conventional conjugation chemistries.
  • Methods of use of stably tethered structures may include detection, diagnosis and/or treatment of a disease or other medical condition.
  • Such conditions may include, but are not limited to, cancer, hyperplasia, diabetic retinopathy, macular degeneration, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, sarcoidosis, asthma, edema, pulmonary hypertension, psoriasis, corneal graft rejection, neovascular glaucoma, Osier- Webber Syndrome, myocardial angiogenesis, plaque neovascularization, restenosis, neointima formation after vascular trauma, telangiectasia, hemophiliac joints, angiofibroma, fibrosis associated with chronic inflammation, lung fibrosis, deep venous thrombosis or wound granulation.
  • the disclosed methods and compositions maybe of use to treat autoimmune disease, such as acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, juvenile diabetes mellitus, Henoch-Schonlein purpura, post- streptococcalnephritis, erythema nodosum, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing autoimmune disease, such as acute i
  • the stably tethered structures may be of use for therapeutic treatment of cancer. It is anticipated that any type of tumor and any type of tumor antigen may be targeted. Exemplary types of tumors that may be targeted include acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal, gastric, head and neck cancer, Hodgkin's lymphoma, lung cancer, medullary thyroid cancer, non-Hodgkin's lymphoma, multiple myeloma, renal cancer, ovarian cancer, pancreatic cancer, glioma, melanoma, liver cancer, prostate cancer, and urinary bladder cancer.
  • Tumor-associated antigens that may be targeted include, but are not limited to, carbonic anhydrase IX, A3, antigen specific for A33 antibody, BrE3-antigen, CDl, CDIa, CD3, CD5, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD79a, CD80, HLA-DR, NCA 95, NCA90, HCG and its subunits, CEA (CEACAM-5), CEACAM-6, CSAp, EGFR, EGP-I, EGP-2, Ep-CAM, Ba 733, HER2/neu, hypoxia inducible factor (HIF), KC4-antigen, KS-I -antigen, KS 1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUCl, MUC2, MUC3, MUC4, PAM-4-antigen, PSA, PSMA, RS5, SlOO, TAG-72, p53,
  • MIF
  • tumor associated antigens include Mizukami et al., (2005, Nature Med. 11 :992-97); Hatfield et al., (2005, Curr. Cancer Drug Targets 5:229-48); Vallbohmer et al. (2005, J. Clin. Oncol. 23:3536-44); and Ren et al. (2005, Ann. Surg. 242:55-63), each incorporated herein by reference.
  • the stably tethered structures may be of use to treat infection with pathogenic organisms, such as bacteria, viruses or fungi.
  • pathogenic organisms such as bacteria, viruses or fungi.
  • fungi include Microsporum, Trichophyton, Epidermopkyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis or Candida albican.
  • viruses include human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, human papilloma virus, hepatitis B virus, hepatitis C virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus or blue tongue virus.
  • HCV human immunodeficiency virus
  • herpes virus cytomegalovirus
  • rabies virus influenza virus
  • human papilloma virus hepatitis B virus
  • Exemplary bacteria include Bacillus anthracis, Streptococcus agalactiae, Legionella pneumophilia, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus spp., Hemophilis influenzae B, Treponema pallidum, Lyme disease spirochetes, Pseudomonas aeruginosa, Mycobacterium leprae, Brucella abortus, Mycobacterium tuberculosis or a Mycoplasma.
  • the precursors incorporated into the monomers, dimers and/or tetramers may comprise one or more proteins, such as a bacterial toxin, a plant toxin, ricin, abrin, a ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, Pseudomonas endotoxin, Ranpirnase (Rap), Rap (N69Q), PE38, dgA, DT390, PLC, tPA, a cytokine, a growth factor, a soluble receptor component, surfactant protein D, IL-4, sIL-4R, sIL-13R, VEGF 121 , TPO, EPO, a clot-dissolving agent, an enzyme, a fluorescent protein
  • an anti-angiogenic agent may form part or all of a precursor or may be attached to a stably tethered structure.
  • exemplary anti-angiogenic agents of use include angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies or peptides, anti- placental growth factor antibodies or peptides, anti-Flk-1 antibodies, anti-Fit- 1 antibodies or peptides, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin 12, IP-IO, Gro- ⁇ , thrombospondin, 2- methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CMlOl, Marimastat, pentosan polysulphate, angiopoietin 2 , interferon-alpha, herbimycin A, PNU145156
  • one or more therapeutic agents such as aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin- 1 , busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-Il), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2-pyrrolinodoxorubicme (2P-DOX), cyano- morpholino doxorubicin, doxorubicin glucuronide, epirubicin
  • one or more effectors such as a diagnostic agent, a therapeutic agent, a chemotherapeutic agent, a radioisotope, an imaging agent, an anti- angiogenic agent, a cytokine, a chemokine, a growth factor, a drug, a prodrug, an enzyme, a binding molecule, a ligand for a cell surface receptor, a chelator, an immunomodulator, an oligonucleotide, a hormone, a photodetectable label, a dye, a peptide, a toxin, a contrast agent, a paramagnetic label, an ultrasound label, a pro-apoptotic agent, a liposome, a nanoparticle or a combination thereof, may be attached to a stably tethered structure.
  • a diagnostic agent such as a therapeutic agent, a chemotherapeutic agent, a radioisotope, an imaging agent, an anti- angiogenic agent, a cyto
  • Such structures may comprise a first and/or second precursor with binding affinity for an antigen selected from the group consisting of CD2, CD3, CD8, CDlO, CD21, CD23, CD24, CD25, CD30, CD33, CD37, CD38, CD40, CD48, CD52, CD55, CD59, CD70, CD74, CD80, CD86, CD138, CD147, HLA-DR, CEA, CSAp, CA-125, TAG-72, EFGR, HER2, HER3, HER4, IGF-IR, c-Met, PDGFR, MUCl, MUC2, MUC3, MUC4, TNFRl, TNFR2, NGFR, Fas (CD95), DR3, DR4, DR5, DR6, VEGF, PIGF, ED-B fibronectin, tenascin, PSMA, PSA, carbonic anhydrase IX, and IL-6.
  • an antigen selected from the group consisting of CD2, CD3, CD8, CDlO, CD21
  • a stably tethered structure of use to induce apoptosis may comprise monoclonal antibodies, Fab fragments, chimeric, humanized or human antibodies or fragments.
  • the stably tethered structure may comprise combinations of anti-CD74 X anti-CD20, anti-CD74 X anti-CD22, anti-CD22 X anti-CD20, anti-CD20 X anti-HLA-DR, anti-CD19 X anti-CD20, anti-CD20 X anti-CD80, anti-CD2 X anti-CD25, anti-CD8 X anti-CD25, and anti-CD2 X anti-CD147.
  • the chimeric, humanized or human antibodies or antibody fragments maybe derived from the variable domains of LL2 (anti-CD22), LLl (anti-CD74) and A20 (anti- CD20).
  • Figure 1 shows two exemplary DDD sequences.
  • the underlined sequence in DDDl corresponds to the first 44 amino-terminal residues found in the RIIa of human PKA.
  • DDD2 (SEQ ID NO:2) differs from DDDl in the two amino acid residues at the N-terminus.
  • Figure 2 shows a schematic diagram for pdHL2-based expression vectors for IgG (upper panel) and C-DDDl -Fab (lower panel).
  • Figure 3 shows a schematic diagram of C-DDD 1-Fab-hMN- 14 and the putative a 2 structure formed by DDDl mediated dimerization.
  • Figure 4 shows a schematic diagram of N-DDD 1-Fab-hMN- 14 and the putative a 2 structure formed by DDDl mediated dimerization.
  • Figure 5 shows the peptide sequence for ADl-C (SEQ ID NO:3).
  • Figure 6 shows SE-HPLC analysis of affinity-purified C-DDD 1-Fab-hMN- 14.
  • Figure 7 shows SDS-PAGE analysis of affinity-purified C-DDDl -Fab-hMN- 14.
  • Figure 8 shows SE-HPLC analysis of affinity-purified N-DDD 1-Fab-hMN- 14.
  • Figure 9 shows C-DDD 1-Fab-hMN- 14 contains two active binding sites.
  • Figure 10 shows N-DDD 1-Fab-hMN- 14 contains two active binding sites
  • Figure 11 shows the binding affinity of C-DDD 1-Fab-hMN- 14 is at least equivalent to the bivalent hMN-14 IgG or F(ab')2 and about 5-fold higher than the monovalent Fab.
  • Figure 12 shows the binding affinity of N-DDD 1-Fab-hMN- 14 is equivalent to bivalent hMN-14 IgG and the binding affinity of C-DDD 1-Fab-hMN- 14 is higher than hMN- 14 IgG.
  • FIG. 13 shows C-DDD 1-Fab-hMN- 14 is stable in pooled human serum with no apparent change in molecular integrity over 96 h.
  • Figure 14 shows C-DDD 1-Fab-hMN- 14 is stable in pooled human serum with unchanged immunoreactivity over 28 h.
  • Figure 15 compares the tumor uptake of C-DDD 1-Fab-hMN- 14 with that of hBS14-l in mice bearing human colorectal cancer xenografts.
  • Figure 16 compares the normal organ uptake of C-DDD 1-Fab-hMN- 14 with that of hBS14-l in mice bearing human colorectal cancer xenografts
  • Figure 17 shows the SE-HPLC analysis of affinity-purified Ra ⁇ -hPAM4-Fab-DDDl.
  • Figure 18 shows the binding affinity of Rap-hPAM4-Fab-DDDl is equivalent to that of hPAM4 IgG.
  • Figure 19 shows the predominant presence of the 3 4 form in N-DDD2-Fab-hMN-14 purified with CBind L (Protein L cellulose).
  • the SE-HPLC trace also reveals the presence of the a2 form, as well as free light chains in both monomelic and dimeric forms.
  • Figure 20 shows the dissociation of the 3 4 form present in purified N-DDD2-Fab- hMN-14 to the a 2 form upon reduction with 5 mM TCEP, which also converts the dimeric light chain to monomelic light chain.
  • Figure 21 shows a schematic representation of the conversion of C-DDD2-Fab-hMN-
  • Figure 22 shows the SE-HPLC analysis of the tetravalent C-DDD2-Fab-hMN-14 after purification by Superdex-200 gel filtration chromatography. Two columns (Biosil SEC 250) were connected in tandem for increased resolution. The tetravalent C-DDD2-Fab-hMN-14 appears as a single peak (indicated as A 4 ) with a retention time of 19.58 min.
  • Figure 23 shows that the tetravalent C-DDD2-Fab-hMN-14 consists of four functional
  • CEA-binding Fab fragments The conditions of SE-HPLC were the same as described for
  • FIG. 22 (a) When WI2 Fab' was mixed with the tetravalent C-DDD2-Fab-hMN-14 at 1:1 molar ratio, four protein peaks representing the binding of the tetravalent C-DDD2-Fab- hMN-14 to one (indicated as 1, at 18.32 min), two (indicated as 2, at 17.45 min) or three
  • Figure 24 shows SE-HPLC analysis of the tetravalent C-DDD2-Fab-hA20 after purification by Superdex-200 gel filtration chromatography.
  • Figure 25 shows cell growth inhibition by the tetravalent C-DDD2-Fab-hA20
  • hA20A4 Daudi (1-1) cells (upper panel) or Ramos cells (lower panel) were resuspended in 48-well plates in duplicate at a final density of 100,000 cells/mL in the complete medium containing 10 nM of hA20, hA20 F(ab') 2 , or hA20A4, in the absence or presence of anti-IgM (0.1 ug/mL). The cells were incubated for 3 days and MTT assay was performed to determine the viable cell populations. Only hA20A4 caused significant growth inhibition (40 to 50 %) in the absence of anti-IgM.
  • Figure 26 shows the presence of the bispecific tetravalent hMN-3xhA20 by ELISA.
  • FIG. 27 shows the presence of bispecific tetravalent hMN-3xhMN-14 by flow cytometry.
  • BXPC3 cells which express high levels of CEACAM6 but only background levels of CEAC AM5, were incubated for 1 h at RT with each of the samples (10ug/mL) in the presence of Alexa-532-WI2, a rat anti-ideotypic mAb for hMN-14 labeled with a fluorescent tag, and analyzed by flow cytometry using Guava PCA. Only the histogram of the sample containing bispecific hMN-3xhMN-14 showed positively stained BXPC3 cells. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
  • An antibody refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an immunologically active (i.e., specifically binding) portion or analog of an immunoglobulin molecule, like an antibody fragment.
  • immunoglobulin molecule e.g., an IgG antibody
  • immunologically active i.e., specifically binding
  • an antibody fragment is a portion of an antibody such as F(ab)2, F(ab')2, Fab, Fv, sFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody.
  • antibody fragment also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.
  • antibody fragments include isolated fragments consisting of the variable regions, such as the "Fv” fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker ("scFv proteins"), and minimal recognition units (CDR) consisting of the amino acid residues that mimic the hypervariable region.
  • Fv variable regions
  • CDR minimal recognition units
  • a therapeutic agent is an atom, molecule, or compound that is useful in the treatment of a disease.
  • therapeutic agents include antibodies, antibody fragments, drugs, toxins, enzymes, nucleases, hormones, immunomodulators, antisense oligonucleotides, small interfering RNA (siRNA), chelators, boron compounds, photoactive agents, dyes, and radioisotopes.
  • siRNA small interfering RNA
  • boron compounds boron compounds
  • photoactive agents dyes, and radioisotopes.
  • a diagnostic agent is an atom, molecule, or compound that is useful in diagnosing a disease.
  • useful diagnostic agents include, but are not limited to, radioisotopes, dyes (such as with the biotin-streptavidin complex), contrast agents, fluorescent compounds or molecules, and enhancing agents (e.g., paramagnetic ions) for magnetic resonance imaging (MRI).
  • An immunoconjugate is a conjugate of a binding molecule (e.g., an antibody component) with an atom, molecule, or a higher-ordered structure (e.g., with a carrier, a therapeutic agent, or a diagnostic agent).
  • a binding molecule e.g., an antibody component
  • an atom, molecule, or a higher-ordered structure e.g., with a carrier, a therapeutic agent, or a diagnostic agent.
  • a naked antibody is an antibody that is not conjugated to any other agent.
  • a carrier is an atom, molecule, or higher-ordered structure that is capable of associating with a therapeutic or diagnostic agent to facilitate delivery of such agent to a targeted cell.
  • Carriers may include lipids (e.g., amphiphilic lipids that are capable of forming higher-ordered structures), polysaccharides (such as dextran), or other higher-ordered structures, such as micelles, liposomes, or nanoparticles.
  • antibody fusion protein is a recombinantly produced antigen- binding molecule in which two or more of the same or different scFv or antibody fragments with the same or different specificities are linked. Valency of the fusion protein indicates how many binding arms or sites the fusion protein has to a single antigen or epitope; i.e., monovalent, bivalent, trivalent or multivalent. The multivalency of the antibody fusion protein means that it can take advantage of multiple interactions in binding to an antigen, thus increasing the avidity of binding to the antigen. Specificity indicates how many antigens or epitopes an antibody fusion protein is able to bind; i.e., monospecific, bispecific, trispecific, multispecific.
  • a natural antibody e.g., an IgG
  • Monospecific, multivalent fusion proteins have more than one binding site for an epitope but only binds to one such epitope, for example a diabody with two binding site reactive with the same antigen.
  • the fusion protein may comprise a single antibody component, a multivalent or multispecific combination of different antibody components, or multiple copies of the same antibody component.
  • the fusion protein may additionally comprise an antibody or an antibody fragment and a therapeutic agent. Examples of therapeutic agents suitable for such fusion proteins include immunomodulators ("antibody-immunomodulator fusion protein") and toxins ("antibody-toxin fusion protein").
  • One preferred toxin comprises a ribonuclease (RNase), preferably a recombinant RNase.
  • An antibody or immunoconjugate preparation, or a composition described herein is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant.
  • An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient mammal, hi particular, an antibody preparation is physiologically significant if its presence invokes an antitumor response or mitigates the signs and symptoms of an autoimmune disease state.
  • a physiologically significant effect could also be the evocation of a humoral and/or cellular immune response in the recipient mammal leading to growth inhibition or death of target cells.
  • Additional moieties can be conjugated to the stably tethered structures described above.
  • drugs, toxins, radioactive compounds, enzymes, hormones, cytotoxic proteins, chelates, cytokines, and other functional agents may be conjugated to the stably tethered structures. Conjugation can be via, for example, covalent attachments to amino acid residues containing amine, carboxyl, thiol or hydroxyl groups in the side-chains .
  • Various conventional linkers may be used for this purpose, for example, diisocyanates, diisothiocyanates, bis(hydroxysuccinimide) esters, carbodiimides, maleimide- hydroxysuccinimide esters, glutaraldehyde and the like.
  • Conjugation of agents to the stably tethered structures preferably does not significantly affect the activity of each subunit contained in the unmodified structures. Conjugation can be carried out separately to the 34 and a' 4 constructs and the resulting conjugates are used for preparing the a2a*2 constructs hi addition, cytotoxic agents may be first coupled to a polymeric carrier, which is then conjugated to a stably tethered structure.
  • conjugates described herein can be prepared by various methods known in the art.
  • a stably tethered structure can be radiolabeled with 131 I and conjugated to a lipid, such that the resulting conjugate can form a liposome.
  • the liposome may incorporate one or more therapeutic (e.g., a drug such as FUdR-dO) or diagnostic agents.
  • a stably tethered structure may be conjugated to 131 I (e.g., at a tyrosine residue) and a drug (e.g., at the epsilon amino group of a lysine residue), and the carrier may incorporate an additional therapeutic or diagnostic agent.
  • Therapeutic and diagnostic agents may be covalently associated with one or more than one subunit of the stably tethered structures.
  • liposomes and micelles are known in the art. See, e.g., Wrobel and Collins, Biochimica et Biophysica Acta (1995), 1235: 296-304; Lundberg et al., J. Pharm. Pharmacol. (1999), 51:1099-1105; Lundberg et al., Int. J. Pharm. (2000), 205:101-108; Lundberg, J. Pharm. Sci. (1994), 83:72-75; Xu et al., Molec. Cancer Ther. (2002), 1:337-346; Torchilin et al., Proc. Nat'l. Acad. Sci., U.S.A. (2003), 100:6039-6044; U.S. 5,565,215; U.S. 6,379,698; and U.S. 2003/0082154.
  • Nanoparticles or nanocapsules formed from polymers, silica, or metals, which are useful for drug delivery or imaging, have been described as well. See, e.g., West et al., Applications of Nanotechnology to Biotechnology (2000), 11:215-217; U.S. 5,620,708; U.S. 5,702,727; and U.S. 6,530,944.
  • the conjugation of antibodies or binding molecules to liposomes to form a targeted carrier for therapeutic or diagnostic agents has been described. See, e.g., Bendas, Biodrugs (2001), 15:215-224; Xu et al., MoI.
  • diagnostic and therapeutic agents can be advantageously used to form the conjugates of the stably tethered structures, or may be linked to haptens that bind to a recognition site on the stably tethered structures.
  • Diagnostic agents may include radioisotopes, enhancing agents for use in MRI or contrast agents for ultrasound imaging, and fluorescent compounds.
  • Many appropriate imaging agents are known in the art, as are methods for their attachment to proteins or peptides (see, e.g., U.S. patents 5,021,236 and 4,472,509, both incorporated herein by reference). Certain attachment methods involve the use of a metal chelate complex employing, for example, an organic chelating agent such a DTPA attached to the protein or peptide (U.S. Patent 4,472,509).
  • Such a carrier can be a polylysine, polysaccharide, or a derivatized or derivatizable polymeric substance having pendant groups to which can be bound chelating groups such as, e.g., ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), porphyrins, polyamines, crown ethers, bis-thiosemicarbazones, polyoximes, and the like known to be useful for this purpose.
  • Carriers containing chelates are coupled to the stably tethered structure using standard chemistries in a way to minimize aggregation and loss of immunoreactivity.
  • the same chelates complexed with non-radioactive metals are useful for MRI, when used along with the stably tethered structures and carriers described herein.
  • Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals, most particularly with radionuclides of gallium, yttrium and copper, respectively.
  • metal-chelate complexes can be made very stable by tailoring the ring size to the metal of interest.
  • Other ring-type chelates, such as macrocyclic polyethers for complexing 223 Ra may be used.
  • Therapeutic agents include, for example, chemotherapeutic drugs such as vinca alkaloids, anthracyclines, epidophyllotoxins, taxanes, antimetabolites, alkylating agents, antibiotics, Cox-2 inhibitors, antimitotics, antiangiogenic and proapoptotic agents, particularly doxorubicin, methotrexate, taxol, CPT-Il, camptothecans, and others from these and other classes of anticancer agents, and the like.
  • chemotherapeutic drugs such as vinca alkaloids, anthracyclines, epidophyllotoxins, taxanes, antimetabolites, alkylating agents, antibiotics, Cox-2 inhibitors, antimitotics, antiangiogenic and proapoptotic agents, particularly doxorubicin, methotrexate, taxol, CPT-Il, camptothecans, and others from these and other classes of anticancer agents, and the like.
  • cancer chemotherapeutic drugs include nitrogen mustards, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, pyrimidine analogs, purine analogs, platinum coordination complexes, hormones, and the like.
  • Suitable chemotherapeutic agents are described in REMINGTON'S PHARMACEUTICAL SCIENCES, 19th Ed. (Mack Publishing Co. 1995), and in GOODMAN AND GILMAN 1 S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th Ed. (MacMillan Publishing Co. 1985), as well as revised editions of these publications.
  • Other suitable chemotherapeutic agents, such as experimental drugs are known to those of skill in the art, and may be conjugated to the stably tethered structures described herein using methods that are known in the art.
  • Another class of therapeutic agents consists of radionuclides that emit ⁇ -particles (such as 212 Pb, 212 Bi, 213 Bi, 211 At, 223 Ra, 225 Ac), ⁇ -particles (such as 32 P, 33 P, 47 Sc, 67 Cu, 67 Ga, 89 Sr, 90 Y, 111 Ag, 125 1, 131 1, 142 Pr, 153 Sm, 161 Tb, 166 Ho, 166 Dy, 177 Lu, 186 Re, 188 Re, 189 Re), or Auger electrons (such as 111 In, 125 1, 67 Ga, 191 Os, 193m Pt, 195m Pt, 195m Hg).
  • the stably tethered structures may be labeled with one or more of the above radionuclides using methods as described for the diagnostic agents.
  • a suitable peptide containing a detectable label e.g., a fluorescent molecule
  • a cytotoxic agent e.g., a radioiodine
  • a therapeutically useful conjugate can be obtained by incorporating a photoactive agent or dye onto the stably tethered structures.
  • Fluorescent compositions, such as fluorochrome, and other chromogens, or dyes, such as porphyrins sensitive to visible light have been used to detect and to treat lesions by directing the suitable light to the lesion. In therapy, this has been termed photoradiation, phototherapy, or photodynamic therapy.
  • the delivery vehicle can be either an a2 (dimer) or an a4 (tetramer) structure with an internalizing antibody binding domain fused to human protamine (peptide of ⁇ 50 amino acid residues) as its precursor.
  • An example of an a2 construct would be VH-CH 1-hPl -DDDl //VL-CL or VH-CH l-hP2-DDDl //VL-CL, where hPl and hP2 are human protamine 1 and human protamine 2, respectively; both capable of forming stable DNA complexes for in vivo applications (Nat Biotechnol. 23: 709- 717, 2005; Gene Therapy. 13: 194-195, 2006).
  • An example of an a4 construct would be VH- CHl-hPl-DDD2//VL-CL or VH-CH l-hP2-DDD2//VL-CL, which would provide four active Fab fragments, each carrying a human protamine for binding to RNAi.
  • the multivalent complex will facilitate the binding to and receptor-mediated internalization into target cells, where the noncovalently bound RNAi is dissociated in the endosomes and released into cytoplasm.
  • the existence of 3 intramolecular disulfide bonds in hPl or hP2 does not present a problem.
  • these constructs may also be of use for targeted delivery of therapeutic genes or DNA vaccines. Another area of use is to apply the A4/A2 technology for producing intrabodies, which is the protein analog of RNAi in terms of function.
  • Various embodiments of the claimed methods and/or compositions may concern one or more peptide based stably tethered structures to be administered to a subject. Administration may occur by any route known in the art, including but not limited to oral, nasal, buccal, inhalational, rectal, vaginal, topical, orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, intraarterial, intrathecal or intravenous injection.
  • Unmodified peptides administered orally to a subject can be degraded in the digestive tract and depending on sequence and structure may exhibit poor absorption across the intestinal lining.
  • methods for chemically modifying peptides to render them less susceptible to degradation by endogenous proteases or more absorbable through the alimentary tract are well known (see, for example, Blondelle et al., 1995, Biophys. J. 69:604- 11; Ecker and Crooke, 1995, Biotechnology 13:351-69; Goodman and Ro, 1995, BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY, VOL. I, ed.
  • peptides may be administered by oral delivery using N-terminal and/or C-terminal capping to prevent exopeptidase activity.
  • the C-terminus may be capped using amide peptides and the N-terminus may be capped by acetylation of the peptide.
  • Peptides may also be cyclized to block exopeptidases, for example by formation of cyclic amides, disulfides, ethers, sulfides and the like.
  • Peptide stabilization may also occur by substitution of D-amino acids for naturally occurring L-amino acids, particularly at locations where endopeptidases are known to act. Endopeptidase binding and cleavage sequences are known in the art and methods for making and using peptides incorporating D-amino acids have been described ⁇ e.g., U.S. Patent Application Publication No. 20050025709, McBride . et al., filed June 14, 2004, incorporated herein by reference). In certain embodiments, peptides and/or proteins may be orally administered by co-formulation with proteinase- and/or peptidase-inhibitors.
  • Excipients of use for orally administered peptides may generally include one or more inhibitors of intestinal proteases/peptidases along with detergents or other agents to improve solubility or absorption of the peptide, which may be packaged within an enteric-coated capsule or tablet (Mehta, 2004).
  • Organic acids may be included in the capsule to acidify the intestine and inhibit intestinal protease activity once the capsule dissolves in the intestine (Mehta, 2004).
  • PEG polyethylene glycol
  • peptides may be modified for oral or inhalational administration by conjugation to certain proteins, such as the Fc region of IgGl (see Examples 3-7).
  • Methods for preparation and use of peptide-Fc conjugates are disclosed, for example, in Low et al. (2005, Hum. Reprod. 20:1805-13) and Dumont et al. (2005, J. Aerosol. Med. 18:294-303), each incorporated herein by reference.
  • Low et al. (2005) disclose the conjugation of the alpha and beta subunits of FSH to the Fc region of IgGl in single chain or heterodimer form, using recombinant expression in CHO cells.
  • the Fc conjugated peptides were absorbed through epithelial cells in the lung or intestine by the neonatal Fc receptor mediated transport system.
  • the Fc conjugated peptides exhibited improved stability and absorption in vivo compared to the native peptides. It was also observed that the heterodimer conjugate was more active than the single chain form.
  • polypeptides or proteins may be used within the scope of the claimed methods and compositions.
  • the proteins may comprise antibodies or fragments of antibodies containing an antigen-binding site.
  • a protein, polypeptide or peptide generally refers, but is not limited to, a protein of greater than about 200 amino acids, up to a foil length sequence translated from a gene; a polypeptide of greater than about 100 amino acids; and/or a peptide of from about 3 to about 100 amino acids.
  • the terms "protein,” “polypeptide” and “peptide” are used interchangeably herein.
  • protein or peptide encompasses amino acid sequences comprising at least one of the 20 common amino acids found in naturally occurring proteins, or at least one modified or unusual amino acid.
  • an "amino acid residue” refers to any naturally occurring amino acid, any amino acid derivative or any amino acid mimic known in the art.
  • the residues of the protein or peptide are sequential, without any non-amino acid interrupting the sequence of amino acid residues.
  • the sequence may comprise one or more non-amino acid moieties.
  • the sequence of residues of the protein or peptide may be interrupted by one or more non-amino acid moieties.
  • protein or peptide encompasses amino acid sequences comprising at least one of the 20 common amino acids found in naturally occurring proteins, or at least one modified or unusual amino acid, including but not limited to those shown below.
  • Proteins or peptides may be made by any technique known to those of skill in the art, including the expression of proteins, polypeptides or peptides through standard molecular biological techniques, the isolation of proteins or peptides from natural sources, or the chemical synthesis of proteins or peptides.
  • the nucleotide and protein, polypeptide and peptide sequences corresponding to various genes have been previously disclosed and may be found at computerized databases known to those of ordinary skill in the art.
  • One such database is the National Center for Biotechnology Information's Genbank and GenPept databases (www.ncbi.nlm.nih.gov/).
  • the coding regions for known genes may be amplified and/or expressed using the techniques disclosed herein or as would be know to those of ordinary skill in the art. Alternatively, various commercial preparations of proteins, polypeptides, and peptides are known to those of skill in the art.
  • peptide mimetics are peptide-containing molecules that mimic elements of protein secondary structure. See, for example, Johnson et al, "Peptide Turn Mimetics” in BIOTECHNOLOGYAND PHARMACY, Pezzuto et al, Eds., Chapman and Hall, New York (1993), incorporated herein by reference.
  • the rationale behind the use of peptide mimetics is that the peptide backbone of proteins exists chiefly to orient amino acid side chains so as to facilitate molecular interactions, such as those of antibody and antigen.
  • a peptide mimetic is expected to permit molecular interactions similar to the natural molecule.
  • fusion proteins These molecules generally have all or a substantial portion of a peptide, linked at the N- or C-terminus, to all or a portion of a second polypeptide or protein.
  • Methods of generating fusion proteins are well known to those of skill in the art.
  • Such proteins may be produced, for example, by chemical attachment using bifunctional cross-linking reagents, by de novo synthesis of the complete fusion protein, or by attachment of a DNA sequence encoding a first protein or peptide to a DNA sequence encoding a second peptide or protein, followed by expression of the intact fusion protein.
  • Proteins or peptides may be synthesized, in whole or in part, in solution or on a solid support in accordance with conventional techniques.
  • Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, (1984, Solid Phase Peptide Synthesis, 2d. ed., Pierce Chemical Co.); Tarn et al, (1983, J. Am. Chem. Soc, 105:6442); Merrifield, (1986, Science, 232: 341- 347); and Barany and Merrifield (1979, The Peptides, Gross and Meienhofer, eds., Academic Press, New York, pp. 1-284).
  • Short peptide sequences usually from about 6 up to about 35 to 50 amino acids, can be readily synthesized by such methods.
  • recombinant DNA technology may be employed wherein a nucleotide sequence which encodes a peptide of interest is inserted into an expression vector, transformed or transfected into an appropriate host cell, and cultivated under conditions suitable for expression.
  • antibody is used herein to refer to any antibody-like molecule that has an antigen binding region, and includes antibody fragments such as Fab', Fab, F(ab') 2 , single domain antibodies (DABs), Fv, scFv (single chain Fv), and the like.
  • Techniques for preparing and using various antibody-based constructs and fragments are well known in the art. Means for preparing and characterizing antibodies are also well known in the art (See, e.g., Harlowe and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory).
  • Antibodies of use may also be commercially obtained from a wide variety of known sources. For example, a variety of antibody secreting hybridoma lines are available from the American Type Culture Collection (ATCC, Manassas, VA).
  • Some embodiments of the claimed methods and/or compositions may concern antibody fragments.
  • Such antibody fragments may be obtained by pepsin or papain digestion of whole antibodies by conventional methods.
  • antibody fragments may be produced by enzymatic cleavage of antibodies with pepsin to provide F(ab') 2 fragments .
  • This fragment may be further cleaved using a thiol reducing agent and, optionally, followed by a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce Fab' monovalent fragments.
  • an enzymatic cleavage using papain n produces two monovalent Fab fragments and an Fc fragment.
  • Fv fragments comprise an association of VH and VL chains. This association can be noncovalent, as described in Inbar et al., 1972, Proc. Natl. Acad. Sci. USA, 69:2659.
  • the variable chains may be linked by an intermolecular disulfide bond or cross-linked by chemicals such as glutaraldehyde. See Sandhu, 1992, Crit. Rev. Biotech., 12:437.
  • the Fv fragments comprise VH and VL chains connected by a peptide linker.
  • These single-chain antigen binding proteins are prepared by constructing a structural gene comprising DNA sequences encoding the VH and VL domains, connected by an oligonucleotides linker sequence. The structural gene is inserted into an expression vector that is subsequently introduced into a host cell, such as E. coli. The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains. Methods for producing sFv's are well-known in the art.
  • CDR peptides (“minimal recognition units") can be obtained by constructing genes encoding the CDR of an antibody of interest. Such genes are prepared, for example, by using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells. See Larrick et al., 1991, Methods: A Companion to Methods in Enzymology 2:106; Ritter et al.
  • a chimeric antibody is a recombinant protein in which the variable regions of a human antibody have been replaced by the variable regions of, for example, a mouse antibody, including the complementarity-determining regions (CDRs) of the mouse antibody.
  • Chimeric antibodies exhibit decreased immunogenicity and increased stability when administered to a subject.
  • Methods for constructing chimeric antibodies are well known in the art (e.g., Leung et al. 5 1994, Hybridoma 13:469).
  • a chimeric monoclonal antibody may be humanized by transferring the mouse CDRs from the heavy and light variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody.
  • the mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences.
  • one or more human FR residues may be replaced by the mouse counterpart residues.
  • Humanized monoclonal antibodies may be used for therapeutic treatment of subjects.
  • the affinity of humanized antibodies for a target may also be increased by selected modification of the CDR sequences (WO0029584A1). Techniques for production of humanized monoclonal antibodies are well known in the art.
  • Other embodiments may concern non-human primate antibodies.
  • General techniques for raising therapeutically useful antibodies in baboons may be found, for example, in Goldenberg et al., WO 91/11465 (1991), and in Losman et al., Int. J. Cancer 46: 310 (1990).
  • the phage display technique may be used to generate human antibodies (e.g., Dantas-Barbosa et al., 2005, Genet. MoI. Res. 4:126-40, incorporated herein by reference).
  • Human antibodies may be generated from normal humans or from humans that exhibit a particular disease state, such as cancer (Dantas-Barbosa et al., 2005).
  • the advantage to constructing human antibodies from a diseased individual is that the circulating antibody repertoire may be biased towards antibodies against disease-associated antigens.
  • RNAs were converted to cDNAs and used to make Fab cDNA libraries using specific primers against the heavy and light chain immunoglobulin sequences (Marks et al., 1991, J. MoI. Biol. 222:581-97, incorporated herein by reference).
  • transgenic animals that have been genetically engineered to produce human antibodies may be used to generate antibodies against essentially any immunogenic target, using standard immunization protocols.
  • a non-limiting example of such a system is the XenoMouse® (e.g., Green et al., 1999, J. Immunol. Methods 231:11-23, incorporated herein by reference) from Abgenix (Fremont, CA).
  • the mouse antibody genes have been inactivated and replaced by functional human antibody genes, while the remainder of the mouse immune system remains intact.
  • the XenoMouse® was transformed with germline-configured YACs (yeast artificial chromosomes) that contained portions of the human IgH and Igkappa loci, including the majority of the variable region sequences, along accessory genes and regulatory sequences.
  • the human variable region repertoire may be used to generate antibody producing B cells, which may be processed into hybridomas by known techniques.
  • a XenoMouse® immunized with a target antigen will produce human antibodies by the normal immune response, which may be harvested and/or produced by standard techniques discussed above.
  • a variety of strains of XenoMouse® are available, each of which is capable of producing a different class of antibody.
  • Such human antibodies may be coupled to other molecules by chemical cross- linking or other known methodologies.
  • Transgenically produced human antibodies have been shown to have therapeutic potential, while retaining the pharmacokinetic properties of normal human antibodies (Green et al., 1999).
  • the skilled artisan will realize that the claimed compositions and methods are not limited to use of the XenoMouse® system but may utilize any transgenic animal that has been genetically engineered to produce human antibodies.
  • One strategy for use of bi-specific stably tethered constructs includes pre-targeting methodologies, in which an effector molecule is administered to a subject after a bi-specific construct has been administered.
  • the bi-specific construct which would include a binding site for an effector, hapten or carrier and one for the diseased tissue, localizes to the diseased tissue and increases the specificity of localization of the effector to the diseased tissue (U.S. Patent Application No. 20050002945). Because the effector molecule may be cleared from circulation much more rapidly than the bi-specific construct, normal tissues may have a decreased exposure to the effector molecule when a pre-targeting strategy is used than when the effector molecule is directly linked to the disease targeting antibody.
  • Pre-targeting methods have been developed to increase the targetbackground ratios of detection or therapeutic agents. Examples of pre-targeting and biotin/avidin approaches are described, for example, in Goodwin et al., U.S. Pat. No. 4,863,713; Goodwin et al., J. Nucl. Med. 29:226, 1988; Hnatowich et al., J. Nucl. Med. 28:1294, 1987; Oehr et al., J. Nucl. Med. 29:728, 1988; Klibanov et al., J. Nucl. Med. 29:1951, 1988; Sinitsyn et al., J. Nucl. Med.
  • bi-specif ⁇ c constructs and targetable constructs may be of use in treating and/or imaging normal or diseased tissue and organs, for example using the methods described in U.S. Pat. Nos.
  • a precursor for construct formation may comprise an aptamer.
  • Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Patent Nos. 5,582,981, 5,595,877 and 5,637,459, each incorporated herein by reference.
  • Aptamers may be prepared by any known method, including synthetic, recombinant, and purification methods, and may be used alone or in combination with other ligands specific for the same target, hi general, a minimum of approximately 3 nucleotides, preferably at least 5 nucleotides, are necessary to effect specific binding. Aptamers of sequences shorter than 10 bases maybe feasible, although aptamers of 10, 20, 30 or 40 nucleotides maybe preferred.
  • Aptamers need to contain the sequence that confers binding specificity, but may be extended with flanking regions and otherwise derivatized.
  • the binding sequences of aptamers may be flanked by primer-binding sequences, facilitating the amplification of the aptamers by PCR or other amplification techniques.
  • the flanking sequence may comprise a specific sequence that preferentially recognizes or binds a moiety to enhance the immobilization of the aptamer to a substrate.
  • Aptamers may be isolated, sequenced, and/or amplified or synthesized as conventional DNA or RNA molecules.
  • aptamers of interest may comprise modified oligomers. Any of the hydroxyl groups ordinarily present in aptamers may be replaced by phosphonate groups, phosphate groups, protected by a standard protecting group, or activated to prepare additional linkages to other nucleotides, or may be conjugated to solid supports.
  • One or more phosphodiester linkages may be replaced by alternative linking groups, such as P(O)O replaced by P(O)S, P(O)NR 2 , P(O)R, P(O)OR 1 , CO, or CNR 2 , wherein R is H or alkyl (1-20C) and R 1 is alkyl (1-20C); in addition, this group may be attached to adjacent nucleotides through O or S. Not all linkages in an oligomer need to be identical.
  • the precursors, components and/or complexes described herein may comprise one or more avimer sequences.
  • Avimers are a class of binding proteins somewhat similar to antibodies in their affinities and specificities for various target molecules. They were developed from human extracellular receptor domains by in vitro exon shuffling and phage display. (Silverman et al., 2005, Nat. Biotechnol. 23:1493-94; Silverman et al., 2006, Nat. Biotechnol. 24:220.)
  • the resulting multidomain proteins may comprise multiple independent binding domains that may exhibit improved affinity (in some cases sub- nanomolar) and specificity compared with single-epitope binding proteins.
  • avimers may be attached to, for example, DDD sequences for use in the claimed methods and compositions. Additional details concerning methods of construction and use of avimers are disclosed, for example, in U.S. Patent Application Publication Nos. 20040175756, 20050048512, 20050053973, 20050089932 and 20050221384, the Examples section of each of which is incorporated herein by reference. Methods of Disease Tissue Detection, Diagnosis and Imaging Protein-Based In Vitro Diagnosis
  • a stably tethered structure comprising an antibody, fusion protein, or fragment thereof may be utilized in liquid phase or bound to a solid-phase carrier, as described below.
  • the antibody or fragment thereof is humanized.
  • the antibody or fragment thereof is fully human.
  • the fusion protein comprises a humanized or fully human antibody.
  • Stably tethered structures incorporating antibodies, fusion proteins, antibody fragments and/or other binding moieties may also be used to detect the presence of a target antigen in tissue sections prepared from a histological specimen.
  • Such in situ detection can be used to determine the presence of the antigen and to determine the distribution of the antigen in the examined tissue.
  • In situ detection can be accomplished by applying a detectably- labeled structure to frozen or paraffin-embedded tissue sections. General techniques of in situ detection are well-known to those of ordinary skill.
  • Stably tethered structures can be detectably labeled with any appropriate marker moiety, for example, a radioisotope, an enzyme, a fluorescent label, a dye, a chromogen, a chemiluminescent label, a bioluminescent label or a paramagnetic label.
  • a marker moiety for example, a radioisotope, an enzyme, a fluorescent label, a dye, a chromogen, a chemiluminescent label, a bioluminescent label or a paramagnetic label.
  • the marker moiety may be a radioisotope that is detected by such means as the use of a gamma counter or a beta-scintillation counter or by autoradiography.
  • the diagnostic conjugate is a gamma-, beta- or a positron-emitting isotope.
  • a marker moiety refers to a molecule that will generate a signal under predetermined conditions. Examples of marker moieties include radioisotopes, enzymes, fluorescent labels, chemiluminescent labels, bioluminescent labels and paramagnetic labels. The binding of marker moieties to stably tethered structures can be accomplished using standard techniques known to the art.
  • Stably tethered structures may, in some embodiments, incorporated nucleic acid moieties.
  • nucleic acids may be analyzed to determine levels of binding, particularly using nucleic acid amplification methods.
  • Various forms of amplification are well known in the art and any such known method may be used.
  • amplification involves the use of one or more primers that hybridize selectively or specifically to a target nucleic acid sequence to be amplified.
  • primer as defined herein, is meant to encompass any nucleic acid that is capable of priming the synthesis of a nascent nucleic acid in a template-dependent process.
  • Computerized programs for selection and design of amplification primers are available from commercial and/or public sources well known to the skilled artisan.
  • a number of template dependent processes are available to amplify the marker sequences present in a given sample.
  • One of the best-known amplification methods is the polymerase chain reaction (referred to as PCR), which is described in detail in U.S. Patent Nos. 4,683,195, 4,683,202 and 4,800,159.
  • PCR polymerase chain reaction
  • other methods of amplification are known and may be used.
  • Methods of diagnostic imaging with labeled peptides or MAbs are well-known.
  • ligands or antibodies are labeled with a gamma-emitting radioisotope and introduced into a patient.
  • a gamma camera is used to detect the location and distribution of gamma-emitting radioisotopes.
  • PET isotopes positron-emitting radionuclides
  • an energy of 511 keV such as 18 F, 68 Ga, 64 Cu, and 124 I.
  • imaging can be conducted by direct labeling of the stably tethered structure, or by a pretargeted imaging method, as described in Goldenberg et al, "Antibody Pre-targeting Advances Cancer Radioimmunodetection and Radioimmunotherapy,” ( J Clin Oncol 2006;24:823-834), see also U.S. Patent Publication Nos. 20050002945, 20040018557, 20030148409 and 20050014207, each incorporated herein by reference.
  • the radiation dose delivered to the patient is maintained at as low a level as possible through the choice of isotope for the best combination of minimum half-life, minimum retention in the body, and minimum quantity of isotope which will permit detection and accurate measurement.
  • radioisotopes that are appropriate for diagnostic imaging include 99m Tc and 111 In.
  • the stably tethered structures, or haptens or carriers that bind to them, also can be labeled with paramagnetic ions and a variety of radiological contrast agents for purposes of in vivo diagnosis.
  • Contrast agents that are particularly useful for magnetic resonance imaging comprise gadolinium, manganese, dysprosium, lanthanum, or iron ions. Additional agents include chromium, copper, cobalt, nickel, rhenium, europium, terbium, holmium, or neodymium.
  • ligands, antibodies and fragments thereof can also be conjugated to ultrasound contrast/enhancing agents.
  • one ultrasound contrast agent is a liposome that comprises a humanized IgG or fragment thereof.
  • the ultrasound contrast agent is a liposome that is gas filled.
  • Non-limiting examples of paramagnetic ions of potential use as imaging agents include chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and erbium (III), with gadolinium being particularly preferred.
  • Ions useful in other contexts, such as X-ray imaging include but are not limited to lanthanum (III), gold (III), lead (II), and especially bismuth (III).
  • Radioisotopes of potential use as imaging or therapeutic agents include astatine 211 , carbon 14 , chromium 51 , chlorine 36 , cobalt 57 , cobalt 58 , copper 62 , copper 64 , copper 67 , Eu 152 , fluorine 18 , gallium 67 , gallium 68 , hydrogen 3 , iodine 123 , iodine 124 , iodine 125 , iodine 131 , indium 111 , iron 52 , iron 59 , lutetium 177 , phosphorus32, phosphorus 33 , rhenium 186 , rhenium 188 , Sc 47 , selenium 75 , silver 111 , sulphur 35 , technetium 94 " 1 , technetium” 111 , yttrium 86 and yttrium 90 , and zirconium 89 .
  • I 125 is often being preferred for use in
  • Radioactively labeled proteins or peptides may be produced according to well-known methods in the art. For instance, they can be iodinated by contact with sodium or potassium iodide and a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent, such as lactoperoxidase.
  • a chemical oxidizing agent such as sodium hypochlorite
  • an enzymatic oxidizing agent such as lactoperoxidase.
  • Proteins or peptides may be labeled with technetium- 99 " 1 by ligand exchange process, for example, by reducing pertechnate with stannous solution, chelating the reduced technetium onto a Sephadex column and applying the peptide to this column or by direct labeling techniques, e.g., by incubating pertechnate, a reducing agent such as SNCl 2 , a buffer solution such as sodium-potassium phthalate solution, and the peptide.
  • a reducing agent such as SNCl 2
  • a buffer solution such as sodium-potassium phthalate solution
  • Intermediary functional groups which are often used to bind radioisotopes which exist as metallic ions to peptides include diethylenetriaminepentaacetic acid (DTPA), DOTA, NOTA, porphyrin chelators and ethylene diaminetetracetic acid (EDTA). Also contemplated for use are fluorescent labels, including rhodamine, fluorescein isothiocyanate and renographin.
  • DTPA diethylenetriaminepentaacetic acid
  • DOTA DOTA
  • NOTA porphyrin chelators
  • EDTA ethylene diaminetetracetic acid
  • fluorescent labels including rhodamine, fluorescein isothiocyanate and renographin.
  • the proteins or peptides may be linked to a secondary binding ligand or to an enzyme (an enzyme tag) that will generate a colored product upon contact with a chromogenic substrate.
  • suitable enzymes include urease, alkaline phosphatase, (horseradish) hydrogen peroxidase and glucose oxidase.
  • Preferred secondary binding ligands are biotin and avidin or streptavidin compounds. The use of such labels is well known to those of skill in the art in light and is described, for example, in U.S.
  • These fluorescent labels are preferred for in vitro uses, but may also be of utility in in vivo applications, particularly endoscopic or intravascular detection procedures.
  • ligands, antibodies, or other proteins or peptides may be tagged with a fluorescent marker.
  • photodetectable labels include Alexa 350, Alexa 430, AMCA, aminoacridine, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, S-carboxy ⁇ ' ⁇ '-dichloro ⁇ 'J 1 - dimethoxy fluorescein, 5-carboxy-2',4',5',7'-tetrachlorofluorescein, 5-carboxyfluorescein, 5- carboxyrhodamine, 6-carboxyrhodamine, 6-carboxytetramethyl amino, Cascade Blue, Cy2, Cy3, Cy5,6-FAM, dansyl chloride, Fluorescein, HEX, 6-JOE, NBD (7-nitrobenz-2-oxa-l
  • Chemiluminescent labeling compounds of use may include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester, or a bioluminescent compound such as luciferin, luciferase and aequorin. Diagnostic conjugates may be used, for example, in intraoperative, endoscopic, or intravascular tumor or disease diagnosis.
  • labels of use may comprise metal nanoparticles.
  • Methods of preparing nanoparticles are known. ⁇ See e.g., U.S. Patent Nos. 6,054,495; 6,127,120; 6,149,868; Lee and Meisel, J. Phys. Chem. 86:3391-3395, 1982.) Nanoparticles may also be obtained from commercial sources ⁇ e.g., Nanoprobes Inc., Yaphank, NY; Polysciences, Inc., Warrington, PA). Modified nanoparticles are available commercially, such as Nanogold® nanoparticles from Nanoprobes, Inc. (Yaphank, NY). Functionalized nanoparticles of use for conjugation to proteins or peptides maybe commercially obtained. Therapeutic agents
  • a stably tethered structure and/or one or more other therapeutic agents may be administered to a subject, such as a subject with cancer.
  • Such agents may be administered in the form of pharmaceutical compositions.
  • this will entail preparing compositions that are essentially free of impurities that could be harmful to humans or animals.
  • a pharmaceutical composition can be administered to a subject by various routes including, for example, orally or parenterally, such as intravenously.
  • an effective amount of a therapeutic agent must be administered to the subject.
  • An "effective amount" is the amount of the agent that produces a desired effect. An effective amount will depend, for example, on the efficacy of the agent and on the intended effect. For example, a lesser amount of an antiangiogenic agent may be required for treatment of a hyperplastic condition, such as macular degeneration or endometriosis, compared to the amount required for cancer therapy in order to reduce or eliminate a solid tumor, or to prevent or reduce its metastasizing.
  • An effective amount of a particular agent for a specific purpose can be determined using methods well known to those in the art.
  • chemotherapeutic agents may be administered.
  • Anti-cancer chemotherapeutic agents of use include, but are not limited to, 5-fluorouracil, bleomycin, busulfan, camptothecins, carboplatin, chlorambucil, cisplatin (CDDP), cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, estrogen receptor binding agents, etoposide (VP 16), farnesyl-protein transferase inhibitors, gemcitabine, ifosfamide, mechlorethamine, melphalan, methotrexate, mitomycin, navelbine, nitrosurea, plicomycin, procarbazine, raloxifene, tamoxifen, taxol, temazolomide (an aqueous form of DTIC), transplatinum, vinblastine and methotrexate, vincristine, or any analog or derivative variant of the for
  • Chemotherapeutic agents of use against infectious organisms include, but are not limited to, acyclovir, albendazole, amantadine, amikacin, amoxicillin, amphotericin B, ampicillin, aztreonam, azithromycin, bacitracin, bactrim, Batrafen®, bifonazole, carbenicillin, caspofungin, cefaclor, cefazolin, cephalosporins, cefepime, ceftriaxone, cefotaxime, chloramphenicol, cidofovir, Cipro®, clarithromycin, clavulanic acid, clotrimazole, cloxacillin, doxycycline, econazole, erythrocycline, erythromycin, flagyl, fluconazole, flucytosine, foscaraet, furazolidone, ganciclovir, gentamycin, imipenem, isoniazid, itraconazole
  • Chemotherapeutic agents and methods of administration, dosages, etc. are well known to those of skill in the art (see for example, the “Physicians Desk Reference”, Goodman & Gilman's “The Pharmacological Basis of Therapeutics” and in “Remington's Pharmaceutical Sciences", incorporated herein by reference in relevant parts). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • Corticosteroid hormones can increase the effectiveness of other chemotherapy agents, and consequently, they are frequently used in combination treatments.
  • Prednisone and dexamethasone are examples of corticosteroid hormones.
  • Progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate, have been used in cancers of the endometrium and breast.
  • Estrogens such as diethylstilbestrol and ethinyl estradiol have been used in cancers such as prostate cancer.
  • Antiestrogens such as tamoxifen have been used in cancers such as breast cancer.
  • Androgens such as testosterone propionate and fluoxymesterone have also been used in treating breast cancer.
  • anti-angiogenic agents such as angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-PlGF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Fit- 1 antibodies and peptides, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP-10, Gro- ⁇ , thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CMlOl, Marimastat, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470
  • immunomodulator includes cytokines, stem cell growth factors, lymphotoxins and hematopoietic factors, such as interleukins, colony-stimulating factors, interferons (e.g., interferons- ⁇ , - ⁇ and - ⁇ ) and the stem cell growth factor designated "Sl factor.”
  • suitable immunomodulator moieties include IL-2, IL-6, IL-10, IL- 12, IL- 18, IL-21, interferon-gamma, TNF-alpha, and the like.
  • cytokine is a generic term for proteins or peptides released by one cell population which act on another cell as intercellular mediators.
  • examples of cytokines include lymphokines, monokines, growth factors and traditional polypeptide hormones.
  • cytokines include growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; prostaglandin, fibroblast growth factor; prolactin; placental lactogen, OB protein; tumor necrosis factor- ⁇ and - ⁇ ; mullerian- inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF- ⁇ ; platelet-growth factor; transforming growth factors (TGFs) such as TGF- ⁇ and TGF- ⁇ ; insulin-like growth factor-I and -II; erythropoiet
  • Chemokines generally act as chemoattractants to recruit immune effector cells to the site of chemokine expression.
  • Chemokines include, but are not limited to, RANTES, MCAF, MIPl -alpha, MIPl -Beta, and IP-IO.
  • RANTES RANTES
  • MCAF MIPl -alpha
  • MIPl -Beta MIPl -Beta
  • IP-IO IP-IO
  • the peptides and/or proteins may be of use in radionuclide therapy or radioimmunotherapy methods (see, e.g., Govindan et al., 2005, Technology in Cancer Research & Treatment, 4:375-91; Sharkey and Goldenberg, 2005, J. Nucl. Med. 46:115S-127S; Goldenberg et al. ( J Clin Oncol 2006; 24:823-834), "Antibody Pre-targeting Advances Cancer Radioimmunodetection and Radioimmunotherapy," each incorporated herein by reference.)
  • stably tethered structures may be directly tagged with a radioisotope of use and administered to a subject.
  • radioisotope(s) may be administered in a pre-targeting method as discussed above, using a haptenic peptide or ligand that is radiolabeled and injected after administration of a bispecific stably tethered structure that localizes at the site of elevated expression in the diseased tissue.
  • Radioactive isotopes useful for treating diseased tissue include, but are not limited to- 111 In 9 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 67 Cu, 90 Y, 125 I, 131 I 5 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 142 Pr, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, 109 Pd, 143 Pr, 149 Pm, 169 Er, 194 Ir, 198 Au, 199 Au, and 211 Pb.
  • the therapeutic radionuclide preferably has a decay energy in the range of 20 to 6,000 keV, preferably in the ranges 60 to 200 keV for an Auger emitter, 100-2,500 keV for a beta emitter, and 4,000-6,000 keV for an alpha emitter.
  • Maximum decay energies of useful beta- particle-emitting nuclides are preferably 20-5,000 keV, more preferably 100-4,000 keV, and most preferably 500-2,500 keV. Also preferred are radionuclides that substantially decay with Auger-emitting particles.
  • beta- particle-emitting nuclides are preferably ⁇ l,000 keV, more preferably ⁇ 100 keV, and most preferably ⁇ 70 keV. Also preferred are radionuclides that substantially decay with generation of alpha-particles.
  • Such radionuclides include, but are not limited to: Dy-152, At-211, Bi- 212, Ra-223, Rn-219, Po-215, Bi-211, Ac-225, Fr-221, At-217, Bi-213 and Fm-255. Decay energies of useful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8,000 keV, and most preferably 4,000-7,000 keV.
  • Cu considered one of the more promising radioisotopes for radioimmunotherapy due to its 61.5 hour half-life and abundant supply of beta particles and gamma rays
  • a protein or peptide using the chelating agent, p- bromoacetamido-benzyl-tetraethylaminetetraacetic acid (TETA).
  • TETA p- bromoacetamido-benzyl-tetraethylaminetetraacetic acid
  • 90 Y which emits an energetic beta particle, can be coupled to a peptide, antibody, fusion protein, or fragment thereof, using diethylenetriaminepentaacetic acid (DTPA).
  • DTPA diethylenetriaminepentaacetic acid
  • Additional potential radioisotopes include 11 C, 13 N, 15 O, 75 Br, 198 Au, 224 Ac, 126 I, 133 I, 77 Br, 113m In, 95 Ru, 97 Ru, 103 Ru, 105 Ru, 107 Hg, 203 Hg, 121m Te, 122m Te, 125m Te, 165 Tm, 167 Tm, 168 Tm, 197 Pt, 109 Pd, 105 Rh, 142 Pr, 143 Pr, 161 Tb, 166 Ho, 199 Au, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 Tl, 225 Ac, 76 Br, 169 Yb 5 and the like.
  • a radiosensitizer can be used.
  • the addition of the radiosensitizer can result in enhanced efficacy. Radiosensitizers are described in D. M. Goldenberg (ed.), CANCER THERAPY WITH RADIOLABELED ANTIBODIES, CRC Press (1995), which is incorporated herein by reference in its entirety.
  • the peptide, antibody, antibody fragment, or fusion protein that has a boron addend- loaded carrier for thermal neutron activation therapy will normally be effected in similar ways. However, it will be advantageous to wait until non-targeted immunoconjugate clears before neutron irradiation is performed. Clearance can be accelerated using an antibody that binds to the ligand. See U.S. Pat. No. 4,624,846 for a description of this general principle.
  • boron addends such as carboranes, can be attached to antibodies. Carboranes can be prepared with carboxyl functions on pendant side chains, as is well-known in the art.
  • Attachment of carboranes to a carrier can be achieved by activation of the carboxyl groups of the carboranes and condensation with amines on the carrier.
  • the intermediate conjugate is then conjugated to the antibody.
  • a boron addend is activated by thermal neutron irradiation and converted to radioactive atoms which decay by alpha-emission to produce highly toxic, short-range effects.
  • kits containing components suitable for treating or diagnosing diseased tissue in a patient may contain at least one stably tethered structure. If the composition containing components for administration is not formulated for delivery via the alimentary canal, such as by oral delivery, a device capable of delivering the kit components through some other route may be included.
  • a device capable of delivering the kit components through some other route may be included.
  • kit components may be packaged together or separated into two or more separate containers, hi some embodiments, the containers may be vials that contain sterile, lyophilized formulations of a composition that are suitable for reconstitution.
  • a kit may also contain one or more buffers suitable for reconstitution and/or dilution of other reagents.
  • Other containers that may be used include, but are not limited to, a pouch, tray, box, tube, or the like. Kit components may be packaged and maintained sterilely within the containers. Another component that can be included is instructions to a person using a kit for its use.
  • Example 1 General strategy for producing Fab-based subunits with the DDDl sequence appended to either the C- or N-terminus of the Fd chain.
  • Fab-based subunits with the DDDl sequence (SEQ ID NO:1) appended to either the C- or N-terminus of the Fd chain are produced as fusion proteins.
  • the plasmid vector pdHL2 has been used to produce a number of antibodies and antibody-based constructs. See Gillies et al., J Immunol Methods (1989), 125:191-202; Losman et al., Cancer (Phila) (1997), 80:2660-6.
  • the di-cistronic mammalian expression vector directs the synthesis of the heavy and light chains of IgG.
  • IgG-pdHL2 constructs The vector sequences are mostly identical for many different IgG- pdHL2 constructs, with the only differences existing in the variable domain (VH and VL) sequences.
  • these IgG-pdHL2 expression vectors can be converted into Fd-DDD l-pdHL2 or Fd-DDD2-pdHL2 expression vectors by replacing the coding sequences for the hinge, CH2 and CH3 domains of the heavy chain with a sequence encoding the first 4 residues of the hinge, a 14 residue Gly-Ser linker and the first 44 residues of human RIIa.
  • the shuttle vector CHl-DDDl-pGemT was designed to facilitate the conversion of IgG-pdHL2 vectors ( Figure 2a) to Fd-DDD l-pdHL2 vectors ( Figure 2b), as described below.
  • the CHl domain was amplified by PCR using the pdHL2 plasmid vector as a template.
  • the left PCR primer consists of the upstream (5') of the CHl domain and a SacII restriction endonuclease site, which is 5' of the CHl coding sequence.
  • the right primer consists of the sequence coding for the first 4 residues of the hinge (PKSC) followed by GGGGS with the final two codons (GS) comprising a Bam HI restriction site.
  • the 410 bp PCR amplimer was cloned into the pGemT PCR cloning vector (Promega, Inc.) and clones were screened for inserts in the T7 (5') orientation.
  • a duplex oligonucleotide designated (G 4 S) 2 DDDl, was synthesized by Sigma Genosys (Haverhill, UK) to code for the amino acid sequence of DDDl (SEQ ID NO:1) preceded by 11 residues of the linker peptide, with the first two codons comprising a BamHI restriction site. A stop codon and an Eagl restriction site are appended to the 3 'end.
  • the encoded polypeptide sequence is shown below.
  • the two oligonucleotides designated RIIAl-44 top and RIIA1-44 bottom, which overlap by 30 base pairs on their 3' ends, were synthesized (Sigma Genosys) and combined to comprise the central 154 base pairs of the 174 bp DDDl sequence.
  • the oligonucleotides were annealed and subjected to a primer extension reaction with Taq polymerase.
  • the duplex was amplified by PCR using the following primers: 5'-GGATCCGGAGGTGGCGGGTCTGGCGGAGGT-S' (SEQ ID NO:9)
  • a 190 bp fragment encoding the DDDl sequence was excised from pGemT with BamHI and Notl restriction enzymes and then ligated into the same sites in CHl-pGemT to generate the shuttle vector CHl-DDDl-pGemT.
  • CHl-DDDl can be incorporated into any IgG construct in the pdHL2 vector as follows.
  • the entire heavy chain constant domain is replaced with CHl- DDDl by removing the SacII/Eagl restriction fragment (CH1-CH3) from ⁇ dHL2 and replacing it with the SacII/Eagl fragment of CHl-DDDl, which is excised from the respective pGemT shuttle vector.
  • DDDl is not restricted to the carboxyl terminal end of CHl and can be placed at the amino terminal end of the VH domain, as shown in Example 2.
  • Example 2 Methods for generating a 2 constructs composed of two identical Fab subunits stably linked via the DDDl sequence fused to either the C- or N-terminus of the Fd chain.
  • C-DDD l-Fd-hMN-14-pdHL2 is an expression vector for producing an a 2 construct that comprises two copies of a fusion protein in which the DDDl sequence is linked to hMN- 14 Fab at the C-terminus of the Fd chain via a flexible peptide spacer (Figure 3).
  • the plasmid vector hMN14(I)-pdHL2 which has been used to produce hMN-14 IgG, was converted to C- DDDl-Fd-hMN-14-pdHL2 by digestion with SacII and Eagl restriction endonucleases, to remove the fragment encoding the CH1-CH3 domains, and insertion of the CHl-DDDl fragment, which was excised from the CH1-DDD1-SV3 shuttle vector with SacII and Eagl.
  • N-DDD l-Fd-hMN-14-pdHL2 is an expression vector for producing an a 2 construct that comprises two copies of a fusion protein in which the DDDl sequence is linked to hMN- 14 Fab at the N-terminus of the Fd chain via a flexible peptide spacer ( Figure 4).
  • the expression vector was engineered as follows. The DDDl domain was amplified by PCR using the two primers shown below. 5' CCATGGGCAGCCACATCCAGATCCCGCC -3' (SEQ ID NO:11)
  • hMN-14 Fd sequence was amplified by PCR using the oligonucleotide primers shown below. hMN-14VHleft G4S Bam
  • N-DDD 1-hMN- 14 Fd sequence was excised with Xhol and Eagl restriction enzymes and the 1.28 kb insert fragment was ligated with a vector fragment that was prepared by digestion of C-DDD l-Fd-hMN-14-pdHL2 with those same enzymes.
  • the final expression vector is N-DDD l-Fd-hMN-14-pDHL2.
  • C-DDD l-Fd-hMN-14-pdHL2 and N-DDD l-Fd-hMN-14-pdHL2 vectors were transfected into Sp2/0-derived myeloma cells by electroporation.
  • C-DDD 1-Fd-hMN- 14- pdHL2 is a di-cistronic expression vector, which directs the synthesis and secretion of both hMN-14 kappa light chain and hMN-14 Fd-DDDl, which combine to form C-DDD 1-hMN- 14 Fab.
  • N-DDD 1-hMN- 14-pdHL2 is a di-cistronic expression vector, which directs the synthesis and secretion of both hMN-14 kappa light chain and N-DDD 1-Fd-hMN- 14, which combine to form N-DDDl-Fab-hMN-14.
  • Each fusion protein forms a stable homodimer via the interaction of the DDDl domain.
  • Clones were screened for protein expression by ELISA, using microtitre plates coated with WI2 (a rat anti-id monoclonal antibody to hMN-14) and detection with HRP-conjugated goat anti-human Fab.
  • the initial productivity of the highest producing C-DDD 1-Fab-hMN 14 and N-DDDl-Fab- hMN14 clones was 60 mg/L and 6 mg/L, respectively.
  • ADl-C is a peptide that binds specifically to DDDl -containing a t constructs.
  • the amino acid sequence of ADl-C (SEQ ID NO:3) is shown in Figure 5.
  • ADl-C was coupled to Affigel following reaction of the sulfhydryl group with chloroacetic anhydride. Culture supernatants were concentrated approximately 10-fold by ultrafiltration before loading onto an ADl-C-affigel column. The column was washed to baseline with PBS and C-DDD 1-Fab-hMN- 14 was eluted with 0.1 M Glycine, pH 2.5.
  • the one-step affinity purification yielded about 81 mg of C-DDDl-Fab- hMN-14 from 1.2 liters of roller bottle culture.
  • SE-HPLC analysis Figure 6 of the eluate shows a single protein peak with a retention time (8.7 min) consistent with a 107-kDa protein.
  • the purity was also confirmed by reducing SDS-PAGE ( Figure 7), showing only two bands of molecular size expected for the two polypeptide constituents of C-DDD 1-Fab-hMN- 14.
  • N-DDDl -Fab-hMN-14 was purified as described above for C-DDD 1-Fab-hMN- 14, yielding 10 mg from 1.2 liters of roller bottle culture.
  • SE-HPLC analysis ( Figure 8) of the eluate shows a single protein peak with a retention time (8.77 min) similar to C-DDDl-Fab- hMN-14 and consistent with a 107 kDa protein. Reducing SDS-PAGE shows only two bands attributed to the polypeptide constituents of N-DDD 1-Fab-hMN- 14.
  • C-DDDl-Fab-hMN-14 The binding activity of C-DDDl-Fab-hMN-14 was determined by SE-HPLC analysis of samples in which the test article was mixed with various amounts of WI2.
  • a sample prepared by mixing WI2 Fab and C-DDDl -Fab-hMN-14 at a molar ratio of 0.75 : 1 showed three peaks, which were attributed to unbound C-DDD 1-Fab-hMN 14 (8.71 min.), C-DDDl- Fab-hMN-14 bound to one WI2 Fab (7.95 min.), and C-DDDl -Fab-hMN 14 bound to two WI2 Fabs (7.37 min.).
  • C-DDD 1-Fab-hMN- 14 has been evaluated in mice bearing human colorectal cancer xenografts (LS 174T) and the results ( Figures 15 and 16) were similar to those obtained for hB S 14-1, which is also bivalent for binding to CEA.
  • Example 3 Methods for generating a 2 constructs composed of two identical Fab fusion proteins, each containing ranpirnase (Rap) and the DDDl sequence linked to the N- terminus of the light chain and the C-terminus of the Fd chain, respectively.
  • Rap-hPAM4-Fd-DDDl-pdHL2 is an expression vector for producing an 82 construct that comprises two identical Fab fusion proteins, each containing ranpirnase (Rap) and the DDDl sequence linked to the N-terminus of the light chain and the C-terminus of the Fd chain, respectively.
  • hPAM4 is a humanized monoclonal antibody specific for MUC-I .
  • Rap-hPAM4-Fab-DDDl Production, purification and characterization of Rap-hPAM4-Fab-DDDl [0172]
  • the Ra ⁇ -hPAM4-Fd-DDDl-pdHL2 vector was transfected into NSO myeloma cells by electroporation.
  • Rap-hPAM4-Fd-DDDl-pdHL2 is a di-cistronic expression vector, which directs the synthesis and secretion of both Rap-fused hPAM4 light chain and hPAM4-Fd- DDDl, which combine to form the Rap-Fab fusion protein.
  • Each fusion protein forms a stable homodimer, referred to as Rap-hPAM4-Fab-DDDl, via the interaction of the DDDl domain.
  • Clones were screened for protein expression by ELISA using microtitre plates coated with WS (a rat anti-id monoclonal antibody to hPAM4) and probed with ML98-1 (a mouse monoclonal antibody to Rap) and HRP-conjugated goat anti-mouse Fc.
  • WS a rat anti-id monoclonal antibody to hPAM4
  • ML98-1 a mouse monoclonal antibody to Rap
  • Rap-hPAM4-Fab-DDDl was purified as described above using an ADl-C-affigel column. The initial productivity of the selected clone was about 0.5 mg per liter. SE-HPLC analysis ( Figure 17) of the affinity-purified Rap-hPAM4-Fab-DDDl shows a single protein peak with a retention time (8.15 min) consistent with the expected molecular mass of -130 kDa. The binding affinity of Rap-hPAM4-Fab-DDDl for WS was shown to be similar to that of hPAM4 IgG ( Figure 18).
  • Example 4 Methods for generating 3 4 constructs composed of four identical Fab fusion proteins, each containing the DDD2 sequence linked to the N-terminus of the Fd chain via a peptide spacer.
  • N-DDD2-Fd-hMN-14-pdHL2 is an expression vector for producing an 34 construct, referred to as the tetravalent N-DDD2-Fab-hMN-14 hereafter, that comprises four copies of a fusion protein in which the DDD2 sequence is appended to hMN-14 Fab at the N-terminus of the Fd chain via a flexible peptide spacer.
  • the expression vector was engineered as follows. Two overlapping, complimentary oligonucleotides (DDD2 Top and DDD2 Bottom), which comprise residues 1 - 13 of DDD2, were made synthetically. The oligonucleotides were annealed and phosphorylated with T4 polynucleotide kinase (PNK), resulting in overhangs on the 5' and 3' ends that are compatible for ligation with DNA digested with the restriction endonucleases Ncol and Pstl, respectively
  • the duplex DNA was ligated with a vector fragment, DDDl-hMN14 Fd-SV3 that was prepared by digestion with Ncol and Pstl, to generate the intermediate construct DDD2- hMN14 Fd-SV3.
  • the final expression vector is N-DDD2-Fd-hMN-14- pdHL2.
  • N-DDD2-Fd-hMN-14-pdHL2 vector was transfected into Sp/EEE myeloma cells by electroporation.
  • the di-cistronic expression vector directs the synthesis and secretion of both hMN-14 kappa light chain and N-DDD2-Fd-hMN-14, which combine to form the Fab-based subunit N-DDD2-Fab-hMN14.
  • the cells were plated in 96-well tissue culture plates and transfectant clones were selected with 0.05 ⁇ M methotrexate (MTX).
  • MTX methotrexate
  • Clones were screened for protein expression by ELISA using microtitre plates coated with WI2 (hMN-14 anti-Id) and detection was achieved with goat anti-human Fab-HRP. The highest producing clones had an initial productivity of approximately 10 mg/L.
  • a total of 16 mg of N-DDD2-hMN-14 was purified by protein L affinity chromatography from 1.8 liters of roller bottle culture. Culture supernatants were concentrated approximately 10-fold by ultrafiltration before loading onto a protein L column. The column was washed to baseline with PBS and N-DDD2-Fab-hMN14 was eluted with 1 mM EDTA, 0.1 M NaAc, pH 2.5 and immediately neutralized with Tris-HCl.
  • N-DDD2-Fab-hMN-14 was separated from other molecular forms by gel filtration chromatography using a Superdex -200 column.
  • Example 5 Methods for generating 3 4 constructs composed of four identical Fab fusion proteins, each containing the DDD2 sequence linked to the C-terminus of the Fd chain via a peptide spacer.
  • C-DDD2-Fd-hMN-14-pdHL2 is an expression vector for producing an 3 4 construct, referred to as the tetravalent C-DDD2-Fab-hMN-14 hereafter, that comprises four copies of a fusion protein in which the DDD2 sequence is appended to hMN-14 Fab at the C-terminus of the Fd chain via a flexible peptide spacer.
  • the expression vector was engineered as follows. Two overlapping, complimentary oligonucleotides, which comprise the coding sequence for part of the linker peptide (GGGGSGGGCG) and residues 1 - 13 of DDD2, were made synthetically. The oligonucleotides were annealed and phosphorylated with T4 PNK, resulting in overhangs on the 5' and 3' ends that are compatible for ligation with DNA digested with the restriction endonucleases BamHI and Pstl, respectively. G4S-DDD2 top 5'GATCCGGAGGTGGCGGGTCTGGCGGAGGTTGCGGCCACATCCAGATCCCGCCG GGGCTCACGGAGCTGCTGCA-3' (SEQ ID NO: 17)
  • the duplex DNA was ligated with the shuttle vector CHl-DDDl-pGemT, which was prepared by digestion with BamHI and Pstl, to generate the shuttle vector CH1-DDD2- pGemT.
  • a 507 bp fragment was excised from CHl-DDD2-pGemT with SacII and Eagl and ligated with the IgG expression vector hMN14(I)-pdHL2, which was prepared by digestion with SacII and Eagl.
  • the final expression construct is C-DDD2-Fd-hMN-14- ⁇ dHL2.
  • C-DDD2-Fd-hA20-pdHL2 is an expression vector for producing an 3 4 construct, referred to as the tetravalent C-DDD2-Fab-hA20 hereafter, that comprises four copies of a fusion protein in which the DDD2 sequence is appended to hA20-Fab at the C-terminus of the Fd chain via a flexible peptide spacer.
  • hA20 is a humanized monoclonal antibody specific for CD20.
  • the expression vector was engineered in three steps as follows. First, the expression vector hA20-IgG-pdHL2 was digested with Sac2 and Ndel to yield the 7578-bp fragment. Next, the expression vector C-DDD2-hMN-14-Fd-pdHL2 was digested with Sac2 and Ndell and the 509-bp fragment coding for CH1-DDD2 was isolated. Third, the 7578-bp fragment was ligated with the 509-bp fragment to generate C-DDD2-Fd-hA20- ⁇ hHL2.
  • C-DDD2-Fd-hMN3-pdHL2 is an expression vector for producing an a 4 construct, referred to as the tetravalent C-DDD2-Fab-hMN-3 hereafter, that comprises four copies of a fusion protein in which the DDD2 sequence is appended to hMN3-Fab at the C-terminus of the Fd chain via a flexible peptide spacer.
  • hMN-3 is a humanized monoclonal antibody specific for the N domain of CEA (CEACAM5) or NCA-90 (CEACAM6).
  • the expression vector hMN-3 -IgG-pdHL2 was digested with Sac2 and NgoM4 to yield the 8118-bp fragment.
  • the expression vector C-DDD2-hMN-14-Fd-pdHL2 was digested with Sac2 and NgoM4 and the 509-bp fragment coding for CH1-DDD2 was isolated.
  • the 8118- bp fragment was ligated with the 509-bp fragment to generate C-DDD2-Fd-hMN-3-phHL2.
  • C-DDD2-Fd-hLL2-pdHL2 is an expression vector for producing an 3 4 construct, referred to as the tetravalent C-DDD2-Fab-hLL2 hereafter, that comprises four copies of a fusion protein in which the DDD2 sequence is appended to hLL2-Fab at the C-terminus of the Fd chain via a flexible peptide spacer.
  • hLL2 is a humanized monoclonal antibody specific for CD22.
  • the expression vector was engineered in three steps as follows. First, the expression vector hLL2-IgG-pdHL2 was digested with Sac2 and Ndel to yield the 7578-bp fragment. Next, the expression vector C-DDD2-hMN-14-Fd-pdHL2 was digested with Sac2 and Ndel and the 509-bp fragment coding for CH1-DDD2 was isolated. Third, the 7578-bp fragment was ligated with the 509-bp fragment to generate C-DDD2-Fd-hLL2- ⁇ hHL2.
  • C-DDD2-Fd-hMN-14-pdHL2 vector was transfected into Sp/EEE myeloma cells by electroporation.
  • the di-cistronic expression vector directs the synthesis and secretion of both hMN-14 kappa light chain and C-DDD2-Fd-hMN-14, which combine to form C-DDD2-Fab- hMN14.
  • the cells were plated in 96-well tissue culture plates and transfectant clones were selected with 0.05 ⁇ M methotrexate (MTX).
  • MTX methotrexate
  • Clones were screened for protein expression by ELISA using microtitre plates coated with WI2 (hMN-14 anti-Id) and detection was achieved with goat anti-human Fab-HRP.
  • the highest producing clones had an initial productivity of approximately 100 mg/L, which was 10-fold higher than that of N-DDD2-Fab-hMN-14.
  • a total of 200 mg of C-DDD2-Fab-hMN- 14 was purified by protein L affinity chromatography from 1.8 liters of roller bottle culture as described above for N-DDD2-Fab-hMN-14.
  • the SE-HPLC profile of the Protein L-purified C-DDD2-Fab-hMN-14 was similar to that of N-DDD2-Fab-hMN-14, showing four protein peaks.
  • C-DDD2-Fd-hA20-pdHL2 vector was transfected into NSO myeloma cells by electroporation.
  • the di-cistronic expression vector directs the synthesis and secretion of both hA20 kappa light chain and C-DDD2-Fd-hA20, which combine to form C-DDD2-Fab-hA20.
  • the cells were plated in 96-well tissue culture plates and transfectant clones were selected with 0.05 ⁇ M methotrexate (MTX).
  • MTX methotrexate
  • Clones were screened for protein expression by ELISA using microtitre plates coated with WR2 (a rat anti-id to hA20) and detection was achieved with goat anti-human Fab-HRP. The highest producing clones had an initial productivity of approximately 10 mg/L.
  • the tetravalent C-DDD2-Fab-hA20 was purified from cell culture supernatants produced in roller bottles by Protein L affinity chromatography followed by Superdex-200 gel filtration. The SE-HPLC profile of the tetravalent C-DDD2-Fab-hA20 is shown in Figure 24.
  • the tetravalent C-DDD2-Fab-hA20 showed potent anti-proliferative activity on Daudi and Ramos even in the absence of anti-IgM ( Figure 25).
  • the bivalent hA20 IgG or F(ab')2 was inactive in inhibiting the growth of Daudi or Ramos under the same conditions either in the absence or presence of anti-IgM.
  • the observed anti-proliferative activity of hA20 IgG or F(ab')2 in the presence of anti-IgM was apparently due to that of anti-IgM.
  • C-DDD2-Fd-hMN-3-pdHL2 vector was transfected into NSO myeloma cells by electroporation.
  • the di-cistronic expression vector directs the synthesis and secretion of both hMN-3 kappa light chain and C-DDD2-Fd-hMN-3, which combine to form C-DDD2-Fab- hMN-3.
  • the cells were plated in 96-well tissue culture plates and transfectant clones were selected with 0.05 ⁇ M methotrexate (MTX).
  • MTX methotrexate
  • C-DDD2-Fab-hMN-3 was purified from cell culture supernatants produced in roller bottles by Protein L affinity chromatography followed by Superdex-200 gel filtration. Production and purification of the tetravalent C-DDD2-Fab-hLL2 [0195]
  • C-DDD2-Fd-hLL2- ⁇ dHL2 vector was transfected into Sp2/0-derived myeloma cells by electroporation. The di-cistronic expression vector directs the synthesis and secretion of both hLL2 kappa light chain and C-DDD2-Fd-hLL2, which combine to form C-DDD2-Fab- hLL2.
  • Clones were screened for protein expression by ELISA using microtitre plates coated with WN (a rat anti-id to hLL2) and detection was achieved with goat anti-human Fab-HRP. The highest producing clones had an initial productivity of approximately 15 mg/L.
  • the tetravalent C-DDD2-Fab-hLL2 was purified from cell culture supernatants produced in roller bottles by Protein L affinity chromatography followed by Superdex-200 gel filtration.
  • Example 6 Methods for generating a 2 a' 2 constructs from two distinct 3 4 and a'4 constructs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Nanotechnology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Optics & Photonics (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
PCT/US2006/010762 2004-02-13 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses Ceased WO2006107617A2 (en)

Priority Applications (55)

Application Number Priority Date Filing Date Title
AU2006232920A AU2006232920B2 (en) 2005-04-06 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
EP06748646A EP1874824A4 (en) 2005-04-06 2006-03-24 METHODS OF GENERATING STABLE COMPOUND RELATED COMPLEXES OF HOMODIMERS, HOMOTRATEERS OR DIMER SIZES AND USES THEREOF
CA2604032A CA2604032C (en) 2005-04-06 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
CN200680019840.6A CN101484182B (zh) 2005-04-06 2006-03-24 由同二聚体、同四聚体或二聚体的二聚体组成的稳定连接复合体的生产方法及用途
JP2008505356A JP5011277B2 (ja) 2005-04-06 2006-03-24 ホモダイマー、ホモテトラマーまたはダイマーのダイマーのからなる安定に連結された複合体を発生させるための方法および使用
CA2607056A CA2607056C (en) 2005-10-19 2006-06-29 Methods and compositions for generating bioactive assemblies of increased complexity and uses
PCT/US2006/025499 WO2007046893A2 (en) 2005-10-19 2006-06-29 Methods for generating bioactive assemblies and uses thereof
AU2006302848A AU2006302848C1 (en) 2005-10-19 2006-06-29 Methods and compositions for generating bioactive assemblies of increased complexity and uses
JP2008536564A JP5231231B2 (ja) 2005-10-19 2006-06-29 複雑性が増大した生理活性アセンブリーを生成するための方法および組成物ならびに使用
EP06785922A EP1937851A4 (en) 2005-10-19 2006-06-29 METHOD AND COMPOSITIONS FOR PRODUCING BIOACTIVE GROUPS OF INCREASED COMPLEXITY AND THEIR USE
US11/478,021 US7534866B2 (en) 2005-10-19 2006-06-29 Methods and compositions for generating bioactive assemblies of increased complexity and uses
AU2006330051A AU2006330051B2 (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
CN201610087781.1A CN105709237A (zh) 2005-12-16 2006-12-05 基于免疫球蛋白的多价生物活性装配体
SG200904095-7A SG153825A1 (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
US11/633,729 US7527787B2 (en) 2005-10-19 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
EP06848816.2A EP1959993B1 (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
CA2633486A CA2633486C (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
CN200680052809.2A CN101374546B (zh) 2005-12-16 2006-12-05 基于免疫球蛋白的多价生物活性装配体
JP2008545643A JP5090366B2 (ja) 2005-12-16 2006-12-05 多価イムノグロブリン系生物活性アセンブリー
PCT/US2006/046367 WO2007075270A2 (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
EP13004490.2A EP2674440B1 (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
KR1020087017349A KR101410521B1 (ko) 2005-12-16 2006-12-05 다가 면역글로불린-계 생동성 어셈블리들
HK08110462.0A HK1117761B (en) 2005-12-16 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies
CN201310087033.XA CN103242451B (zh) 2005-12-16 2006-12-05 基于免疫球蛋白的多价生物活性装配体
US11/925,408 US7666400B2 (en) 2005-04-06 2007-10-26 PEGylation by the dock and lock (DNL) technique
US12/396,605 US7858070B2 (en) 2005-10-19 2009-03-03 Multivalent immunoglobulin-based bioactive assemblies
US12/417,917 US7906121B2 (en) 2005-10-19 2009-04-03 Methods and compositions for generating bioactive assemblies of increased complexity and uses
US12/644,146 US7981398B2 (en) 2005-04-06 2009-12-22 PEGylation by the dock and lock (DNL) technique
US12/731,781 US8003111B2 (en) 2005-04-06 2010-03-25 Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo
US12/766,092 US8067006B2 (en) 2005-04-06 2010-04-23 Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US12/871,345 US8551480B2 (en) 2004-02-13 2010-08-30 Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US12/949,536 US8211440B2 (en) 2005-10-19 2010-11-18 Multivalent immunoglobulin-based bioactive assemblies
US13/021,302 US8246960B2 (en) 2005-10-19 2011-02-04 Methods and compositions for generating bioactive assemblies of increased complexity and uses
US13/150,613 US8277817B2 (en) 2005-04-06 2011-06-01 PEGylation by the dock and lock (DNL) technique
US13/178,092 US8158129B2 (en) 2005-04-06 2011-07-07 Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in vivo
US13/246,389 US8338140B2 (en) 2005-04-06 2011-09-27 Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US13/412,816 US8435540B2 (en) 2005-04-06 2012-03-06 Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in VIVO
US13/483,761 US20120276608A1 (en) 2005-10-19 2012-05-30 Multivalent Immunoglobulin-Based Bioactive Assemblies
US13/549,906 US8865176B2 (en) 2005-10-19 2012-07-16 Methods and compositions for generating bioactive assemblies of increased complexity and uses
US13/589,575 US9457100B2 (en) 2005-04-06 2012-08-20 PEGylation by the dock and lock (DNL) technique
US13/670,790 US8889835B2 (en) 2005-04-06 2012-11-07 Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US13/688,812 US8883162B2 (en) 2005-10-19 2012-11-29 Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US13/710,908 US8652484B2 (en) 2004-02-13 2012-12-11 Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US13/851,404 US20130217091A1 (en) 2005-04-06 2013-03-27 Dimeric Alpha Interferon PEGylated Site-Specifically Shows Enhanced and Prolonged Efficacy in Vivo
US14/017,885 US9481878B2 (en) 2004-02-13 2013-09-04 Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US14/488,921 US9169470B2 (en) 2005-10-19 2014-09-17 Methods and compositions for generating bioactive assemblies of increased complexity and uses
US14/505,595 US9862770B2 (en) 2005-10-19 2014-10-03 Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US14/510,746 US9707300B2 (en) 2005-04-06 2014-10-09 Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US14/598,664 US9441043B2 (en) 2005-12-16 2015-01-16 Methods of treating cancer with antibodies that target the insulin-like growth factor type I receptor (IGF-1R)
US14/854,873 US20150374846A1 (en) 2005-10-19 2015-09-15 Methods and Compositions for Generating Bioactive Assemblies of Increased Complexity and Uses
US15/224,882 US9751948B2 (en) 2005-12-16 2016-08-01 Class of monospecific and bispecific humanized antibodies that target the insulin-like growth factor type I receptor (IGF-1R)
US15/247,386 US9872920B2 (en) 2005-04-06 2016-08-25 PEGylation by the dock and lock (DNL) technique
US15/264,747 US20160375108A1 (en) 2004-02-13 2016-09-14 Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity
US15/646,813 US10377829B2 (en) 2005-12-16 2017-07-11 Isolated nucleic acid encoding an anti-IGF-1R antibody
US15/827,637 US20180079816A1 (en) 2005-10-19 2017-11-30 Multivalent Antibody Complexes Targeting IGF-1R Show Potent Toxicity Against Solid Tumors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US66860305P 2005-04-06 2005-04-06
US60/668,603 2005-04-06
US72829205P 2005-10-19 2005-10-19
US60/728,292 2005-10-19
US75119605P 2005-12-16 2005-12-16
US60/751,196 2005-12-16

Related Parent Applications (5)

Application Number Title Priority Date Filing Date
US11/389,358 Continuation-In-Part US7550143B2 (en) 1999-05-10 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
PCT/US2006/010762 Division WO2006107617A2 (en) 2004-02-13 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
PCT/US2006/012084 Continuation-In-Part WO2006107786A2 (en) 2004-02-13 2006-03-29 Improved stably tethered structures of defined compositions with multiple functions or binding specificities
PCT/US2006/025499 Continuation-In-Part WO2007046893A2 (en) 2004-02-13 2006-06-29 Methods for generating bioactive assemblies and uses thereof
US12/871,345 Continuation-In-Part US8551480B2 (en) 2004-02-13 2010-08-30 Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity

Related Child Applications (6)

Application Number Title Priority Date Filing Date
PCT/US2006/010762 Division WO2006107617A2 (en) 2004-02-13 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
US11/391,584 Continuation-In-Part US7521056B2 (en) 1999-05-10 2006-03-28 Stably tethered structures of defined compositions with multiple functions or binding specificities
PCT/US2006/012084 Continuation-In-Part WO2006107786A2 (en) 2004-02-13 2006-03-29 Improved stably tethered structures of defined compositions with multiple functions or binding specificities
US11/478,021 Continuation-In-Part US7534866B2 (en) 1999-05-10 2006-06-29 Methods and compositions for generating bioactive assemblies of increased complexity and uses
US73372906A Continuation-In-Part 2004-02-13 2006-12-05
US11/633,729 Continuation-In-Part US7527787B2 (en) 1999-05-10 2006-12-05 Multivalent immunoglobulin-based bioactive assemblies

Publications (2)

Publication Number Publication Date
WO2006107617A2 true WO2006107617A2 (en) 2006-10-12
WO2006107617A3 WO2006107617A3 (en) 2008-08-14

Family

ID=37073939

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/010762 Ceased WO2006107617A2 (en) 2004-02-13 2006-03-24 Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses

Country Status (7)

Country Link
US (4) US7521056B2 (enExample)
EP (1) EP1874824A4 (enExample)
JP (1) JP5011277B2 (enExample)
CN (1) CN101484182B (enExample)
AU (1) AU2006232920B2 (enExample)
CA (1) CA2604032C (enExample)
WO (1) WO2006107617A2 (enExample)

Cited By (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008001802A1 (en) 2006-06-27 2008-01-03 Asahi Kasei Kabushiki Kaisha Substrate for biological fluid treatment
JP2008308423A (ja) * 2007-06-13 2008-12-25 Gunma Univ 両親媒性の高分子配位子によって安定化された高分子錯体および検査用組成物および医薬組成物
WO2009150284A2 (es) 2008-06-13 2009-12-17 Proyecto De Biomedicina Cima, S.L. Conjugados de apo-a para la administración de compuestos biológicamente activos
US7666400B2 (en) 2005-04-06 2010-02-23 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
WO2010063865A1 (es) 2008-12-03 2010-06-10 Proyecto De Biomedicina Cima, S.L. Uso de modulinas solubles en fenol para el desarrollo de vacunas
EP1959993A4 (en) * 2005-12-16 2010-06-30 Ibc Pharmaceuticals Inc POLYVALENTIC BIOACTIVE ARRANGEMENTS ON IMMUNOGLOBULIN BASIS
EP1937851A4 (en) * 2005-10-19 2010-08-25 Ibc Pharmaceuticals Inc METHOD AND COMPOSITIONS FOR PRODUCING BIOACTIVE GROUPS OF INCREASED COMPLEXITY AND THEIR USE
EP2114985A4 (en) * 2007-02-02 2010-09-22 Baylor Res Inst MULTIVARIABLE ANTIGEN COMPLEXES AND TARGET HUMANIZED MONOCLONAL ANTIBODY
EP2156186A4 (en) * 2007-05-03 2010-11-03 Tethys Bioscience Inc BINDING REAGENTS WITH SMALL EPITOP BINDING MOLECULES
EP2258398A1 (en) 2009-05-26 2010-12-08 Araclón Biotech, S. L. Albumin-amyloid peptide conjugates and uses thereof
US7878978B2 (en) 2004-03-18 2011-02-01 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Use of relaxin to increase arterial compliance
WO2010139808A3 (en) * 2009-06-05 2011-02-24 Ablynx Nv Monovalent, bivalent and trivalent anti human respiratory syncytial virus (hrsv) nanobody constructs for the prevention and/or treatment of respiratory tract infections
JP2011506344A (ja) * 2007-12-06 2011-03-03 ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド インフルエンザウイルスに対する抗体およびその使用方法
US7901680B2 (en) 2005-10-19 2011-03-08 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
US7906121B2 (en) 2005-10-19 2011-03-15 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US7906118B2 (en) 2005-04-06 2011-03-15 Ibc Pharmaceuticals, Inc. Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology
WO2011029980A1 (es) 2009-09-11 2011-03-17 Proyecto De Biomedicina Cima, S.L. Composiciones terapéuticas para el tratamiento de enfermedades causadas por hpv
CN102066974A (zh) * 2008-04-30 2011-05-18 免疫医疗公司 用于蛋白、肽和其他分子的f-18标记的改进方法和组合物
US8003111B2 (en) 2005-04-06 2011-08-23 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo
WO2011101332A1 (en) 2010-02-16 2011-08-25 Proyecto De Biomedicina Cima, S.L. Compositions based on the fibronectin extracellular domain a for the treatment of melanoma
US8034396B2 (en) 2008-04-01 2011-10-11 Tyco Healthcare Group Lp Bioadhesive composition formed using click chemistry
US8034352B2 (en) 2005-04-06 2011-10-11 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
US8067006B2 (en) 2005-04-06 2011-11-29 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US8158129B2 (en) 2005-04-06 2012-04-17 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in vivo
JP2012516683A (ja) * 2009-02-04 2012-07-26 ソンギュングヮン ユニバーシティ ファウンデーション フォー コーポレート コラボレーション 細胞内の伝達能が増加した低分子干渉ｒｎａ複合体
US8236934B2 (en) 2007-02-02 2012-08-07 Baylore Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
WO2012123269A1 (en) 2011-03-11 2012-09-20 Proyecto De Biomedicina Cima, S.L. Immunogenic compositions and methods for their use
EP2505640A1 (en) 2011-03-29 2012-10-03 Neo Virnatech, S.L. Vaccine compositions for birnavirus-borne diseases
US8349332B2 (en) 2005-04-06 2013-01-08 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
US8435539B2 (en) 2004-02-13 2013-05-07 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
EP2606897A1 (en) 2011-12-22 2013-06-26 Laboratorios Del. Dr. Esteve, S.A. Methods and compositions for the treatment of diseases caused by enveloped viruses
US8475794B2 (en) 2005-04-06 2013-07-02 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases
US8481041B2 (en) 2005-04-06 2013-07-09 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US8491914B2 (en) 2004-02-13 2013-07-23 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for delivery of interference RNA
US8512728B2 (en) 2009-02-21 2013-08-20 Sofradim Production Method of forming a medical device on biological tissue
US8535477B2 (en) 2009-02-21 2013-09-17 Sofradim Production Medical devices incorporating functional adhesives
US8551480B2 (en) 2004-02-13 2013-10-08 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US8562988B2 (en) 2005-10-19 2013-10-22 Ibc Pharmaceuticals, Inc. Strategies for improved cancer vaccines
US8652484B2 (en) 2004-02-13 2014-02-18 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US8663689B2 (en) 2009-02-21 2014-03-04 Sofradim Production Functionalized adhesive medical gel
US8865857B2 (en) 2010-07-01 2014-10-21 Sofradim Production Medical device with predefined activated cellular integration
US8877170B2 (en) 2009-02-21 2014-11-04 Sofradim Production Medical device with inflammatory response-reducing coating
US8883162B2 (en) 2005-10-19 2014-11-11 Ibc Pharmaceuticals, Inc. Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US8968733B2 (en) 2009-02-21 2015-03-03 Sofradim Production Functionalized surgical adhesives
US9193780B2 (en) 2008-06-05 2015-11-24 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
WO2015184203A1 (en) 2014-05-29 2015-12-03 Macrogenics, Inc. Tri-specific binding molecules and methods of use thereof
US9247931B2 (en) 2010-06-29 2016-02-02 Covidien Lp Microwave-powered reactor and method for in situ forming implants
US9272029B2 (en) 2009-03-26 2016-03-01 Ibc Pharmaceuticals, Inc. Interferon lambada-antibody complexes
US9315567B2 (en) 2012-08-14 2016-04-19 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US9382329B2 (en) 2012-08-14 2016-07-05 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to Trop-2 expressing cells
US9416197B2 (en) 2013-11-01 2016-08-16 Ibc Pharmaceuticals, Inc. Bispecific antibodies that neutralize both TNF-α and IL-6: novel therapeutic agent for autoimmune disease
US9441043B2 (en) 2005-12-16 2016-09-13 Immunomedics, Inc. Methods of treating cancer with antibodies that target the insulin-like growth factor type I receptor (IGF-1R)
US9446123B2 (en) 2012-06-01 2016-09-20 Ibc Pharmaceuticals, Inc. Multimeric complexes with improved in vivo stability, pharmacokinetics and efficacy
US9481878B2 (en) 2004-02-13 2016-11-01 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
EP2334705B1 (en) * 2008-09-26 2016-12-14 UCB Biopharma SPRL Biological products
WO2017019846A1 (en) 2015-07-30 2017-02-02 Macrogenics, Inc. Pd-1-binding molecules and methods use thereof
US9623115B2 (en) 2005-04-06 2017-04-18 Ibc Pharmaceuticals, Inc. Dock-and-Lock (DNL) Complexes for Disease Therapy
US9644022B2 (en) 2009-11-30 2017-05-09 Ablynx N.V. Amino acid sequences directed against human respiratory syncytial virus (HRSV) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
US9682143B2 (en) 2012-08-14 2017-06-20 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
WO2017106061A1 (en) 2015-12-14 2017-06-22 Macrogenics, Inc. Bispecific molecules having immunoreactivity with pd-1 and ctla-4, and methods of use thereof
US9687547B2 (en) 2015-05-28 2017-06-27 Immunomedics, Inc. T20 constructs for anti-HIV (human immunodeficiency virus) therapy and/or vaccines
WO2017142928A1 (en) 2016-02-17 2017-08-24 Macrogenics, Inc. Ror1-binding molecules, and methods of use thereof
US9775928B2 (en) 2013-06-18 2017-10-03 Covidien Lp Adhesive barbed filament
WO2017180813A1 (en) 2016-04-15 2017-10-19 Macrogenics, Inc. Novel b7-h3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US9862770B2 (en) 2005-10-19 2018-01-09 Ibc Pharmaceuticals, Inc. Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US9931413B2 (en) 2005-04-06 2018-04-03 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
WO2018119166A1 (en) 2016-12-23 2018-06-28 Macrogenics, Inc. Adam9-binding molecules, and methods of use thereof
WO2018162450A1 (en) 2017-03-06 2018-09-13 Fundación Para La Investigación Médica Aplicada New inmunostimulatory compositions comprising an entity of cold inducible rna-binding protein with an antigen for the activation of dendritic cells
US10245321B2 (en) 2012-08-14 2019-04-02 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
US10501552B2 (en) 2015-01-26 2019-12-10 Macrogenics, Inc. Multivalent molecules comprising DR5-binding domains
US10857181B2 (en) 2015-04-21 2020-12-08 Enlivex Therapeutics Ltd Therapeutic pooled blood apoptotic cell preparations and uses thereof
EP3752196A1 (en) 2018-02-15 2020-12-23 MacroGenics, Inc. Variant cd3-binding domains and their use in combination therapies for the treatment of disease
US10982210B2 (en) 2018-03-02 2021-04-20 Sixfold Bioscience Ltd. Compositions for delivery of cargo to cells
US10993990B2 (en) 2014-05-16 2021-05-04 Baylor Research Institute Methods and compositions for treating autoimmune and inflammatory conditions
US11000548B2 (en) 2015-02-18 2021-05-11 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11007251B2 (en) 2015-12-17 2021-05-18 The Johns Hopkins University Ameliorating systemic sclerosis with death receptor agonists
US11072653B2 (en) 2015-06-08 2021-07-27 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11084879B2 (en) 2016-04-07 2021-08-10 The Johns Hopkins University Compositions and methods for treating pancreatitis and pain with death receptor agonists
US11174315B2 (en) 2015-10-08 2021-11-16 Macrogenics, Inc. Combination therapy for the treatment of cancer
WO2022000136A1 (en) * 2020-06-28 2022-01-06 Dingfu Biotarget Co., Ltd. Methods and compositions for cancer treatment
WO2022010798A1 (en) 2020-07-06 2022-01-13 Kiromic BioPharma, Inc. Mesothelin isoform binding molecules and chimeric pd1 receptor molecules, cells containing the same and uses thereof
US11299528B2 (en) 2014-03-11 2022-04-12 D&D Pharmatech Inc. Long acting TRAIL receptor agonists for treatment of autoimmune diseases
US11304976B2 (en) 2015-02-18 2022-04-19 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11318163B2 (en) 2015-02-18 2022-05-03 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
WO2022108627A1 (en) 2020-11-18 2022-05-27 Kiromic Biopharma, Inc.Kiromic Biopharma, Inc. Gamma-delta t cell manufacturing processes and chimeric pd1 receptor molecules
US11357865B2 (en) 2020-04-27 2022-06-14 Sixfold Bioscience Ltd. Compositions containing nucleic acid nanoparticles with modular functionality
US11459394B2 (en) 2017-02-24 2022-10-04 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
US11497767B2 (en) 2015-02-18 2022-11-15 Enlivex Therapeutics R&D Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11512289B2 (en) 2015-02-18 2022-11-29 Enlivex Therapeutics Rdo Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11596652B2 (en) 2015-02-18 2023-03-07 Enlivex Therapeutics R&D Ltd Early apoptotic cells for use in treating sepsis
US11730761B2 (en) 2016-02-18 2023-08-22 Enlivex Therapeutics Rdo Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11767353B2 (en) 2020-06-05 2023-09-26 Theraly Fibrosis, Inc. Trail compositions with reduced immunogenicity
US11795226B2 (en) 2017-12-12 2023-10-24 Macrogenics, Inc. Bispecific CD16-binding molecules and their use in the treatment of disease
US12252582B2 (en) 2019-08-29 2025-03-18 University Of Delaware Biofunctional thiophene monomers and polymers thereof for electronic biomedical devices
US12435155B2 (en) 2020-02-21 2025-10-07 Macrogenics, Inc. CD137 binding molecules and uses thereof

Families Citing this family (229)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875584B1 (en) * 1999-03-02 2005-04-05 University Of Georgia Research Foundation, Inc. Prophylactic and therapeutic immunization against protozoan infection and disease
US7550143B2 (en) * 2005-04-06 2009-06-23 Ibc Pharmaceuticals, Inc. Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
US7527787B2 (en) * 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
US7591994B2 (en) 2002-12-13 2009-09-22 Immunomedics, Inc. Camptothecin-binding moiety conjugates
WO2003074567A2 (en) * 2002-03-01 2003-09-12 Immunomedics, Inc. Internalizing anti-cd74 antibodies and methods of use
US20160279239A1 (en) 2011-05-02 2016-09-29 Immunomedics, Inc. Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease
US7563433B2 (en) * 2007-01-11 2009-07-21 Immunomedics, Inc. Methods and compositions for F-18 labeling of proteins, peptides and other molecules
US7597876B2 (en) * 2007-01-11 2009-10-06 Immunomedics, Inc. Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
US7651689B2 (en) * 2002-11-15 2010-01-26 Albert Einstein College Of Medicine Of Yeshiva University Methods of applying ionization radiation for therapy of infections
EP1587550B1 (en) * 2003-01-31 2011-07-27 Immunomedics, Inc. Methods and compositions for administering therapeutic and diagnostic agents
US20110064754A1 (en) * 2005-03-03 2011-03-17 Center For Molecular Medicine And Immunology Immunoconjugates Comprising Poxvirus-Derived Peptides and Antibodies Against Antigen-Presenting Cells for Subunit-Based Poxvirus Vaccines
US8883160B2 (en) * 2004-02-13 2014-11-11 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for therapeutic and diagnostic use
US9550838B2 (en) 2004-02-13 2017-01-24 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for therapeutic and diagnostic use
US20170088635A1 (en) * 2004-02-13 2017-03-30 Ibc Pharmaceuticals, Inc. Dock-and-Lock (DNL) Complexes for Therapeutic and Diagnostic Use
US20110020273A1 (en) * 2005-04-06 2011-01-27 Ibc Pharmaceuticals, Inc. Bispecific Immunocytokine Dock-and-Lock (DNL) Complexes and Therapeutic Use Thereof
US7888135B2 (en) * 2004-04-23 2011-02-15 University Of Georgia Research Foundation, Inc. Diagnostic assay for Trypanosoma cruzi infection
EP3332808B1 (en) 2005-03-03 2020-09-09 Immunomedics Inc. Humanized l243 antibodies
US10058621B2 (en) 2015-06-25 2018-08-28 Immunomedics, Inc. Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers
US20160355591A1 (en) 2011-05-02 2016-12-08 Immunomedics, Inc. Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies
CN101484182B (zh) * 2005-04-06 2014-06-11 Ibc药品公司 由同二聚体、同四聚体或二聚体的二聚体组成的稳定连接复合体的生产方法及用途
PL1874821T3 (pl) 2005-04-26 2013-09-30 Trion Pharma Gmbh Kombinacja przeciwciał i glikokortykoidów do leczenia raka
US7780969B2 (en) * 2005-07-15 2010-08-24 University Of Georgia Research Foundation, Inc. Trypanosoma cruzi proteome compositions and methods
US20090042235A1 (en) * 2005-08-19 2009-02-12 Shun Hirota Photoregulated peptide, and method for regulation of peptide-protein complex formation using the photoregulated peptide
US20090110680A1 (en) * 2006-04-07 2009-04-30 Stephanie Sieger Combination of an anti ED-B fibronectin domain antibody and gemcitabine
WO2007128557A1 (en) * 2006-05-03 2007-11-15 Bayer Schering Pharma Aktiengesellschaft Combination of an anti edb fibronectin domain antibody l19-sip and an anti-egfr antibody
US8398956B2 (en) 2007-01-11 2013-03-19 Immunomedics, Inc. In vivo copper-free click chemistry for delivery of therapeutic and/or diagnostic agents
US8709382B2 (en) 2007-01-11 2014-04-29 Immunomedics, Inc. Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
US8889100B2 (en) 2007-01-11 2014-11-18 Immunomedics, Inc. Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
US8153100B2 (en) * 2007-01-11 2012-04-10 Immunomedics, Inc. Methods and compositions for F-18 labeling of proteins, peptides and other molecules
US8545809B2 (en) 2007-01-11 2013-10-01 Immunomedics, Inc. Methods and compositions for improved 18F labeling of proteins, peptides and other molecules
AU2007343610C1 (en) * 2007-01-17 2013-11-07 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
CA2700000A1 (en) * 2007-07-30 2009-02-05 Rick L. Tarleton Diagnostic assay for trypanosoma cruzi infection
KR101661770B1 (ko) 2007-09-21 2016-10-04 더 리전트 오브 더 유니버시티 오브 캘리포니아 표적화된 인터페론이 강력한 아폽토시스 및 항-종양 활성을 발휘함
JP5468015B2 (ja) 2008-01-08 2014-04-09 アクセリア ファーマシューティカルズ 抗菌ペプチド系に対する作動薬
WO2009092108A2 (en) * 2008-01-17 2009-07-23 Fox Chase Cancer Center Biomarkers for the diagnosis and treatment of pancreatic cancer
CN102076355B (zh) * 2008-04-29 2014-05-07 Abbvie公司 双重可变结构域免疫球蛋白及其用途
EP2278993A4 (en) * 2008-05-16 2012-09-12 Corthera Inc METHOD FOR PROMOTING HEALING
US20090285757A1 (en) * 2008-05-16 2009-11-19 Northeastern University Methods of targeting cells for diagnosis and therapy
AU2009256246B2 (en) 2008-06-03 2013-07-18 Abbvie Inc. Dual variable domain immunoglobulins and uses thereof
SG191639A1 (en) 2008-06-03 2013-07-31 Abbott Lab Dual variable domain immunoglobulins and uses thereof
AU2009268585C1 (en) 2008-07-08 2014-10-02 Abbvie Inc. Prostaglandin E2 dual variable domain immunoglobulins and uses thereof
US20110174064A1 (en) * 2008-10-02 2011-07-21 Ramot At Tel-Aviv University Ltd. Method and system for emitting light
US9125949B2 (en) * 2008-12-30 2015-09-08 University Of North Texas Direct utilization of plasma proteins for the in vivo assembly of protein-drug/imaging agent conjugates, nanocarriers and coatings for biomaterials
HRP20230487T1 (hr) 2009-02-13 2023-07-21 Immunomedics, Inc. Imunokonjugati s unutarstaničnom vezom koja se može rascijepiti
AU2010215200A1 (en) 2009-02-21 2011-10-13 Sofradim Production Apparatus and method of reaching polymers by exposure to UV radiation to produce injectable medical devices
AU2010215936B2 (en) 2009-02-21 2015-03-05 Covidien Lp Medical devices having activated surfaces
EP2398850B1 (en) 2009-02-21 2018-08-22 Sofradim Production Medical devices with an activated coating
CA2753179A1 (en) 2009-02-21 2010-08-26 Sofradim Production Crosslinked fibers and method of making same by extrusion
EP2398845B1 (en) 2009-02-21 2017-12-13 Sofradim Production Amphiphilic compounds and self-assembling compositions made therefrom
AU2010215199B2 (en) 2009-02-21 2015-01-15 Sofradim Production Compounds and medical devices activated with solvophobic linkers
US9555154B2 (en) 2009-02-21 2017-01-31 Covidien Lp Medical devices having activated surfaces
EP2398943B1 (en) 2009-02-21 2013-04-17 Sofradim Production Crosslinked fibers and method of making same using uv radiation
US9039979B2 (en) 2009-02-21 2015-05-26 Sofradim Production Apparatus and method of reacting polymers passing through metal ion chelated resin matrix to produce injectable medical devices
US8637074B2 (en) * 2009-03-31 2014-01-28 Aphios Corporation Methods for co-encapsulation of combination drugs and co-encapsulated combination drug product
JP6114936B2 (ja) * 2009-08-31 2017-04-19 イミューノメディクス、インコーポレイテッドＩｍｍｕｎｏｍｅｄｉｃｓ， Ｉｎｃ． 強力な細胞毒性活性を示すランピルナーゼ（ｒａｐ）を含む免疫毒素の組成物及び使用方法
TW201119673A (en) * 2009-09-01 2011-06-16 Abbott Lab Dual variable domain immunoglobulins and uses thereof
CN102482701B (zh) 2009-09-16 2015-05-13 免疫医疗公司 I类抗-cea抗体及其使用
UY32948A (es) * 2009-10-15 2011-02-28 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
WO2011050263A2 (en) * 2009-10-23 2011-04-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Systemic immunosuppression in the treatment of age related macular degeneration and diabetic retinopathy
UY32979A (es) 2009-10-28 2011-02-28 Abbott Lab Inmunoglobulinas con dominio variable dual y usos de las mismas
AU2010315432A1 (en) * 2009-11-05 2012-04-12 Center For Molecular Medicine And Immunology Immunoconjugates comprising poxvirus-derived peptides and antibodies against antigen-presenting cells for subunit-based poxvirus vaccines
CN101876658B (zh) * 2009-11-25 2013-08-28 华中科技大学 一种具有多价效应和纳米尺寸效应的多肽荧光探针的构建方法及其应用
CA2782194C (en) 2009-12-02 2018-01-16 Immunomedics, Inc. Combination of radiolabelled antibodies (rait) and antibody-drug conjugates (adc) for treatment of pancreatic cancer
SMT202100234T1 (it) 2009-12-04 2021-05-07 Oncoc4 Lnc Usi di inibitori di fattori inducibili da ipossia
JP5789821B2 (ja) 2009-12-04 2015-10-07 イミューノメディクス、インコーポレイテッドＩｍｍｕｎｏｍｅｄｉｃｓ， Ｉｎｃ． タンパク質、ペプチドおよび他の分子の改善されたｆ−１８標識化のための方法および組成物
EP2509630A4 (en) * 2009-12-09 2013-07-17 Immunomedics Inc SYSTEM FOR PROCESSING CYTOTOXIC REMEDIES THROUGH BISPECIFIC ANTIBODY TARGET
EP2518078B1 (en) * 2009-12-15 2020-05-20 Choe, Muhyeon Method for manufacturing dimers and multimers by increasing the production of bond bridges in a complex of multiple monomers and repeating chains of an affinity domain of a type specifically binding to protein monomers
AU2011203890B2 (en) * 2010-01-11 2013-05-30 Center For Molecular Medicine And Immunology Enhanced cytotoxicity of anti-CD74 and anti-HLA-DR antibodies with interferon-gamma
US20110243841A1 (en) * 2010-04-01 2011-10-06 Immunomedics, Inc. Antibody-Based Depletion of Antigen-Presenting Cells and Dendritic Cells
US9272074B2 (en) 2010-03-25 2016-03-01 Sofradim Production Surgical fasteners and methods for sealing wounds
AU2011231245B2 (en) 2010-03-25 2015-03-26 Covidien Lp Medical devices incorporating functional adhesives
CA2805987C (en) 2010-07-27 2019-04-09 Sofradim Production Polymeric fibers having tissue reactive members
TW201206473A (en) 2010-08-03 2012-02-16 Abbott Lab Dual variable domain immunoglobulins and uses thereof
CA2808211C (en) * 2010-08-17 2018-08-28 Ibc Pharmaceuticals, Inc. Combination therapy with anti-cd74 antibodies provides enhanced toxicity to malignancies, autoimmune disease and other diseases
CN103260639A (zh) 2010-08-26 2013-08-21 Abbvie公司 双重可变结构域免疫球蛋白及其用途
TW201302793A (zh) 2010-09-03 2013-01-16 Glaxo Group Ltd 新穎之抗原結合蛋白
US9675693B2 (en) 2010-09-30 2017-06-13 Riken Methods and drugs targeting Eva1 or Ceacam1 gene expression for treatment and diagnosing of glioma
AU2011323354B2 (en) * 2010-11-03 2014-07-31 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
JP6024025B2 (ja) 2011-05-02 2016-11-09 イミューノメディクス、インコーポレイテッドＩｍｍｕｎｏｍｅｄｉｃｓ， Ｉｎｃ． 少容量投与用のアロタイプ選択抗体の限外濾過濃縮
WO2012162583A1 (en) * 2011-05-26 2012-11-29 Ibc Pharmaceuticals, Inc. Design and construction of novel multivalent antibodies
US20140155581A1 (en) * 2011-07-06 2014-06-05 Medimmune, Llc Methods For Making Multimeric Polypeptides
US20130058947A1 (en) 2011-09-02 2013-03-07 Stem Centrx, Inc Novel Modulators and Methods of Use
CN102559636B (zh) * 2011-12-30 2014-03-12 百泰生物药业有限公司 用于白血病和自身免疫疾病的抗体融合蛋白及其制备方法
WO2013102042A2 (en) 2011-12-30 2013-07-04 Abbvie Inc. Dual specific binding proteins directed against il-13 and/or il-17
WO2013188740A1 (en) 2012-06-14 2013-12-19 Ambrx, Inc. Anti-psma antibodies conjugated to nuclear receptor ligand polypeptides
US10131712B2 (en) 2012-08-14 2018-11-20 Ibc Pharmaceuticals, Inc. Combination therapy with T-cell redirecting bispecific antibodies and checkpoint inhibitors
HK1212359A1 (en) 2012-11-01 2016-06-10 Abbvie Inc. Anti-vegf/dll4 dual variable domain immunoglobulins and uses thereof
WO2014089354A1 (en) 2012-12-07 2014-06-12 The Regents Of The University Of California Cd138-targeted interferon demonstrates potent apoptotic and anti-tumor activities
PL2900277T3 (pl) 2012-12-13 2022-05-16 Immunomedics, Inc. Dawkowanie immunokoniugatów przeciwciał i sn-38 dla poprawy skuteczności i zmniejszenia toksyczności
US10047163B2 (en) 2013-02-08 2018-08-14 Abbvie Stemcentrx Llc Multispecific constructs
WO2014143383A1 (en) 2013-03-13 2014-09-18 Agilent Technologies, Inc. Transposome tethered to a gene delivery vehicle
KR102090356B1 (ko) * 2013-03-15 2020-03-18 메모리얼 슬로안 케터링 캔서 센터 다량체화 기술
JP2016522793A (ja) 2013-03-15 2016-08-04 アッヴィ・インコーポレイテッド ＩＬ−１βおよび／またはＩＬ−１７に対して指向された二重特異的結合タンパク質
WO2014194100A1 (en) 2013-05-29 2014-12-04 The Regents Of The University Of California Anti-cspg4 fusions with interferon for the treatment of malignancy
CN103382224B (zh) * 2013-06-28 2015-03-18 英科隆生物技术（杭州）有限公司 含有四聚体形式的异源交联抗体的异源交联物及其应用
CN104650237B (zh) * 2013-06-28 2019-08-20 英科隆生物技术（杭州）有限公司 一种交联抗体及其在免疫检测中应用
CN103897064B (zh) * 2013-11-29 2016-05-11 广州优联康医药科技有限公司 长效重组人绒促性素融合蛋白
JOP20200094A1 (ar) 2014-01-24 2017-06-16 Dana Farber Cancer Inst Inc جزيئات جسم مضاد لـ pd-1 واستخداماتها
JOP20200096A1 (ar) 2014-01-31 2017-06-16 Children’S Medical Center Corp جزيئات جسم مضاد لـ tim-3 واستخداماتها
US11039621B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US11039620B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US9622483B2 (en) 2014-02-19 2017-04-18 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
JP6447933B2 (ja) 2014-02-21 2019-01-09 アイビーシー ファーマスーティカルズ，インコーポレイテッド Ｔｒｏｐ−２発現細胞に対する免疫応答を誘発することによる疾患治療
US9139649B2 (en) 2014-02-25 2015-09-22 Immunomedics, Inc. Humanized anti-CD22 antibody
ME03558B (me) 2014-03-14 2020-07-20 Novartis Ag Molekuli anti-lag-3 antiтela i njihove upotrebe
WO2015142675A2 (en) 2014-03-15 2015-09-24 Novartis Ag Treatment of cancer using chimeric antigen receptor
WO2015200260A1 (en) 2014-06-24 2015-12-30 Immunomedics, Inc. Anti-histone therapy for vascular necrosis in severe glomerulonephritis
WO2016014565A2 (en) 2014-07-21 2016-01-28 Novartis Ag Treatment of cancer using humanized anti-bcma chimeric antigen receptor
BR112017001242A2 (pt) 2014-07-21 2017-12-05 Novartis Ag tratamento de câncer usando um receptor antigênico quimérico a cd33
JP2017528433A (ja) 2014-07-21 2017-09-28 ノバルティス アーゲー 低い免疫増強用量のｍＴＯＲ阻害剤とＣＡＲの組み合わせ
WO2016014553A1 (en) 2014-07-21 2016-01-28 Novartis Ag Sortase synthesized chimeric antigen receptors
US20170209492A1 (en) 2014-07-31 2017-07-27 Novartis Ag Subset-optimized chimeric antigen receptor-containing t-cells
JP6919118B2 (ja) 2014-08-14 2021-08-18 ノバルティス アーゲー ＧＦＲα−４キメラ抗原受容体を用いる癌の治療
MY189028A (en) 2014-08-19 2022-01-20 Novartis Ag Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment
CA2961636A1 (en) 2014-09-17 2016-03-24 Boris ENGELS Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
AU2015328370B2 (en) 2014-10-07 2021-08-05 Immunomedics, Inc. Neoadjuvant use of antibody-drug conjugates
MX389663B (es) 2014-10-14 2025-03-20 Novartis Ag Moleculas de anticuerpo que se unen a pd-l1 y usos de las mismas.
US20180334490A1 (en) 2014-12-03 2018-11-22 Qilong H. Wu Methods for b cell preconditioning in car therapy
WO2016094881A2 (en) 2014-12-11 2016-06-16 Abbvie Inc. Lrp-8 binding proteins
JP6862343B2 (ja) * 2014-12-19 2021-04-21 アブリンクス エン．ヴェー． システイン結合ナノボディダイマー
IL254817B2 (en) 2015-04-08 2023-12-01 Novartis Ag Cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car) - expressing cell
CA2981543A1 (en) 2015-04-22 2016-10-27 Immunomedics, Inc. Isolation, detection, diagnosis and/or characterization of circulating trop-2-positive cancer cells
WO2016172583A1 (en) 2015-04-23 2016-10-27 Novartis Ag Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
TW201710286A (zh) 2015-06-15 2017-03-16 艾伯維有限公司 抗ｖｅｇｆ、ｐｄｇｆ及／或其受體之結合蛋白
PT3313443T (pt) 2015-06-25 2023-08-30 Immunomedics Inc Combinação de anticorpos anti-hla-dr ou anti-trop-2 com inibidores de microtúbulos, inibidores de parp, inibidores de bruton quinase ou inibidores de fosfoinositídeo 3-quinase melhora significativamente o resultado terapêutico no cancro
PL3316885T3 (pl) 2015-07-01 2021-12-06 Immunomedics, Inc. Immunokoniugaty przeciwciało-sn-38 z linkerem cl2a
CN115112898A (zh) * 2015-07-15 2022-09-27 加州理工学院 Il-17f-特异性捕获剂、组合物以及使用和制造的方法
US20180222982A1 (en) 2015-07-29 2018-08-09 Novartis Ag Combination therapies comprising antibody molecules to pd-1
DK3317301T3 (da) 2015-07-29 2021-06-28 Immutep Sas Kombinationsterapier omfattende antistofmolekyler mod lag-3
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
JP2019502695A (ja) 2015-12-17 2019-01-31 ノバルティス アーゲー ＰＤ−１に対する抗体分子とＣ−Ｍｅｔ阻害剤との組合せおよびその使用
EP3389712B1 (en) 2015-12-17 2024-04-10 Novartis AG Antibody molecules to pd-1 and uses thereof
MA44140A (fr) 2015-12-22 2021-05-19 Dana Farber Cancer Inst Inc Récepteur d'antigène chimérique (car) contre la mésothéline et anticorps contre l'inhibiteur de pd-l1 pour une utilisation combinée dans une thérapie anticancéreuse
WO2017125897A1 (en) 2016-01-21 2017-07-27 Novartis Ag Multispecific molecules targeting cll-1
CA3016287A1 (en) 2016-03-04 2017-09-08 Novartis Ag Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
EP3432924A1 (en) 2016-03-23 2019-01-30 Novartis AG Cell secreted minibodies and uses thereof
SI3443096T1 (sl) 2016-04-15 2023-07-31 Novartis Ag Sestavki in postopki za selektivno izražanje himerni antigenskih receptorjev
EP3464375A2 (en) 2016-06-02 2019-04-10 Novartis AG Therapeutic regimens for chimeric antigen receptor (car)- expressing cells
WO2017214151A1 (en) 2016-06-06 2017-12-14 Northwestern University Fusion protein construct
US10669338B2 (en) 2016-06-17 2020-06-02 Immunomedics, Inc. Anti-PD-1 checkpoint inhibitor antibodies that block binding of PD-L1 to PD-1
CN120285179A (zh) 2016-07-15 2025-07-11 诺华股份有限公司 使用与激酶抑制剂组合的嵌合抗原受体治疗和预防细胞因子释放综合征
IL264486B2 (en) 2016-07-28 2025-04-01 Novartis Ag Combination therapies of chimeric antigen receptors and PD-1 inhibitors
SG11201900885VA (en) 2016-08-01 2019-02-27 Novartis Ag Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
US12158399B2 (en) 2016-08-05 2024-12-03 Duke University CaMKK2 inhibitor compositions and methods of using the same
CN106267191A (zh) * 2016-09-03 2017-01-04 山西纳安生物科技有限公司 纳米抗体生物药透皮给药制剂系统及制备方法和应用
EP3523331A1 (en) 2016-10-07 2019-08-14 Novartis AG Chimeric antigen receptors for the treatment of cancer
JOP20190100A1 (ar) 2016-11-19 2019-05-01 Potenza Therapeutics Inc بروتينات ربط مولد ضد مضاد لـ gitr وطرق استخدامها
EP4043485A1 (en) 2017-01-26 2022-08-17 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
US20200048359A1 (en) 2017-02-28 2020-02-13 Novartis Ag Shp inhibitor compositions and uses for chimeric antigen receptor therapy
WO2018187074A1 (en) 2017-04-03 2018-10-11 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
WO2018197451A1 (en) * 2017-04-24 2018-11-01 Advanced Accelerator Applications Accelerator-driven neutron activator for brachytherapy
EP3615055A1 (en) 2017-04-28 2020-03-04 Novartis AG Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
WO2018201051A1 (en) 2017-04-28 2018-11-01 Novartis Ag Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
CA3062439A1 (en) * 2017-05-05 2018-11-08 Memorial Sloan Kettering Cancer Center Modular self assembly disassembly (sada) technologies
EP3641812A1 (en) 2017-06-22 2020-04-29 Novartis AG Antibody molecules to cd73 and uses thereof
AU2018292618A1 (en) 2017-06-27 2019-12-19 Novartis Ag Dosage regimens for anti-TIM-3 antibodies and uses thereof
EP3652209A2 (en) 2017-07-11 2020-05-20 Compass Therapeutics LLC Agonist antibodies that bind human cd137 and uses thereof
KR20250025039A (ko) 2017-07-20 2025-02-20 노파르티스 아게 항-lag-3 항체의 투여 요법 및 그의 용도
TWI635559B (zh) * 2017-07-25 2018-09-11 春田科技顧問股份有限公司 裝載埠的吹淨裝置及其吹淨方法
ES2963157T3 (es) 2017-07-26 2024-03-25 Forty Seven Inc Anticuerpos anti-SIRP-alfa y métodos relacionados
WO2019089753A2 (en) 2017-10-31 2019-05-09 Compass Therapeutics Llc Cd137 antibodies and pd-1 antagonists and uses thereof
AU2018368731A1 (en) 2017-11-16 2020-05-14 Novartis Ag Combination therapies
US11851497B2 (en) 2017-11-20 2023-12-26 Compass Therapeutics Llc CD137 antibodies and tumor antigen-targeting antibodies and uses thereof
JP7653013B2 (ja) 2018-01-04 2025-03-28 アイコニック セラピューティクス リミテッド ライアビリティ カンパニー 抗組織因子抗体、抗体薬物コンジュゲート、及び関連する方法
EP3737692A4 (en) 2018-01-09 2021-09-29 Elstar Therapeutics, Inc. CALRETICULIN AND MODIFIED T-LYMPHOCYTES BINDING CONSTRUCTIONS FOR THE TREATMENT OF DISEASES
CA3090249A1 (en) 2018-01-31 2019-08-08 Novartis Ag Combination therapy using a chimeric antigen receptor
TWI786265B (zh) * 2018-02-02 2022-12-11 美商再生元醫藥公司 用於表徵蛋白質二聚合之系統及方法
US12152073B2 (en) 2018-03-14 2024-11-26 Marengo Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
WO2019183131A1 (en) 2018-03-19 2019-09-26 Bioventures, Llc Periostin antibodies and methods of using the same
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
US20210047405A1 (en) 2018-04-27 2021-02-18 Novartis Ag Car t cell therapies with enhanced efficacy
AU2019272575A1 (en) 2018-05-21 2020-12-10 Compass Therapeutics Llc Compositions and methods for enhancing the killing of target cells by NK cells
WO2019226658A1 (en) 2018-05-21 2019-11-28 Compass Therapeutics Llc Multispecific antigen-binding compositions and methods of use
US12128099B2 (en) 2018-05-25 2024-10-29 Bioventures, Llc Myxoma virus compositions and methods of use
US20210213063A1 (en) 2018-05-25 2021-07-15 Novartis Ag Combination therapy with chimeric antigen receptor (car) therapies
US20210214459A1 (en) 2018-05-31 2021-07-15 Novartis Ag Antibody molecules to cd73 and uses thereof
AU2019284911A1 (en) 2018-06-13 2020-12-17 Novartis Ag BCMA chimeric antigen receptors and uses thereof
US20210238268A1 (en) 2018-06-19 2021-08-05 Atarga, Llc Antibody molecules to complement component 5 and uses thereof
AU2019297451A1 (en) 2018-07-03 2021-01-28 Marengo Therapeutics, Inc. Anti-TCR antibody molecules and uses thereof
AR116109A1 (es) 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
WO2020035577A1 (en) 2018-08-16 2020-02-20 Cantargia Ab Anti-il1rap antibody compositions
MX2021005594A (es) 2018-11-13 2021-10-22 Compass Therapeutics Llc Constructos multiespecificos de union contra moleculas de puntos de control y usos de los mismos.
WO2020106880A1 (en) 2018-11-20 2020-05-28 Bioventures, Llc Cells for the production of viruses and methods of using the same
JP2022513255A (ja) 2018-12-20 2022-02-07 ノバルティス アーゲー ＨＤＭ２－ｐ５３相互作用阻害剤とＢＣＬ２阻害剤との組み合わせ及び癌を処置するためのその使用
WO2020128972A1 (en) 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
ES3032659T3 (en) 2019-02-15 2025-07-23 Novartis Ag 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
ES2982474T3 (es) 2019-02-15 2024-10-16 Novartis Ag Derivados de 3-(1-oxoisoindolin-2-il)piperidin-1,6-diona sustituidos y usos de estos
US10871640B2 (en) 2019-02-15 2020-12-22 Perkinelmer Cellular Technologies Germany Gmbh Methods and systems for automated imaging of three-dimensional objects
EP3927747A1 (en) 2019-02-21 2021-12-29 Marengo Therapeutics, Inc. Antibody molecules that bind to nkp30 and uses thereof
CN119661722A (zh) 2019-02-21 2025-03-21 马伦戈治疗公司 结合t细胞相关癌细胞的多功能分子及其用途
US20220088075A1 (en) 2019-02-22 2022-03-24 The Trustees Of The University Of Pennsylvania Combination therapies of egfrviii chimeric antigen receptors and pd-1 inhibitors
PH12021552414A1 (en) 2019-03-29 2022-07-25 Atarga Llc Anti fgf23 antibody
EP4004037A1 (en) 2019-07-26 2022-06-01 Vanderbilt University Human monoclonal antibodies to enterovirus d68
JP7629906B2 (ja) 2019-08-15 2025-02-14 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 細胞標的化のための多重特異性抗原結合分子およびそれらの使用
CN114786679A (zh) 2019-10-21 2022-07-22 诺华股份有限公司 具有维奈托克和tim-3抑制剂的组合疗法
CN114786680A (zh) 2019-10-21 2022-07-22 诺华股份有限公司 Tim-3抑制剂及其用途
CA3163104A1 (en) 2019-11-26 2021-06-03 Novartis Ag Chimeric antigen receptors and uses thereof
MX2022007759A (es) 2019-12-20 2022-07-19 Novartis Ag Combinacion del anticuerpo anti tim-3 mbg453 y anticuerpo anti tgf-beta nis793, con o sin decitabina o el anticuerpo anti pd-1 spartalizumab, para el tratamiento de mielofibrosis y sindrome mielodisplasico.
GB2609554B (en) 2020-01-03 2025-08-20 Marengo Therapeutics Inc Anti-TCR antibody molecules and uses thereof
US20210222244A1 (en) 2020-01-17 2021-07-22 Becton, Dickinson And Company Methods and compositions for single cell secretomics
EP4090335A1 (en) 2020-01-17 2022-11-23 Novartis AG Combination comprising a tim-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
AU2021220847A1 (en) 2020-02-11 2022-09-01 Vanderbilt University Human monoclonal antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2)
BR112022016633A2 (pt) 2020-02-27 2022-12-13 Novartis Ag Métodos para produzir células que expressam receptor de antígeno quimérico
TWI896628B (zh) 2020-03-26 2025-09-11 美國凡德貝爾大學 針對嚴重急性呼吸症候群冠狀病毒２(SARS-CoV-2)之人單株抗體
WO2021195385A1 (en) 2020-03-26 2021-09-30 Vanderbilt University HUMAN MONOCLONAL ANTIBODIES TO SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-GoV-2)
CN111500586B (zh) * 2020-05-21 2022-11-04 昆明理工大学 特异结合狂犬病毒l蛋白加帽区的核酸适配体及其应用
MX2022015852A (es) 2020-06-23 2023-01-24 Novartis Ag Regimen de dosificacion que comprende derivados de 3-(1-oxoisoindolin-2-il)piperidina-2,6-diona.
PH12023550015A1 (en) 2020-07-16 2024-03-11 Novartis Ag Anti-betacellulin antibodies, fragments thereof, and multi-specific binding molecules
WO2022026592A2 (en) 2020-07-28 2022-02-03 Celltas Bio, Inc. Antibody molecules to coronavirus and uses thereof
EP4188549A1 (en) 2020-08-03 2023-06-07 Novartis AG Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US20230321285A1 (en) 2020-08-31 2023-10-12 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
EP4204020A1 (en) 2020-08-31 2023-07-05 Advanced Accelerator Applications International S.A. Method of treating psma-expressing cancers
CN112156194B (zh) * 2020-09-29 2023-01-24 中国工程物理研究院核物理与化学研究所 一种去除177Lu溶液中内毒素的方法
US20240002509A1 (en) 2020-11-06 2024-01-04 Novartis Ag ANTIBODY Fc VARIANTS
CA3198447A1 (en) 2020-11-13 2022-05-19 Novartis Ag Combination therapies with chimeric antigen receptor (car)-expressing cells
JP2024505049A (ja) 2021-01-29 2024-02-02 ノバルティス アーゲー 抗ｃｄ７３及び抗ｅｎｔｐｄ２抗体のための投与方式並びにその使用
TW202304979A (zh) 2021-04-07 2023-02-01 瑞士商諾華公司 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途
AR125874A1 (es) 2021-05-18 2023-08-23 Novartis Ag Terapias de combinación
CN113403384A (zh) * 2021-06-22 2021-09-17 南昌大学 动脉粥样硬化生物标志物及其应用
EP4405396A2 (en) 2021-09-20 2024-07-31 Voyager Therapeutics, Inc. Compositions and methods for the treatment of her2 positive cancer
US20250034559A1 (en) 2021-11-17 2025-01-30 Voyager Therapeutics, Inc. Compositions and methods for the treatment of tau-related disorders
TW202342548A (zh) 2022-02-07 2023-11-01 美商威特拉公司 抗獨特型(anti-idiotype)抗體分子及其用途
GB202204813D0 (en) 2022-04-01 2022-05-18 Bradcode Ltd Human monoclonal antibodies and methods of use thereof
EP4522757A2 (en) 2022-05-13 2025-03-19 Voyager Therapeutics, Inc. Compositions and methods for the treatment of her2 positive cancer
TW202435912A (zh) 2022-08-03 2024-09-16 美商航海家醫療公司 用於穿過血腦屏障之組合物及方法
WO2024168061A2 (en) 2023-02-07 2024-08-15 Ayan Therapeutics Inc. Antibody molecules binding to sars-cov-2
WO2025122634A1 (en) 2023-12-05 2025-06-12 Voyager Therapeutics, Inc. Compositions and methods for the treatment of tau-related disorders
WO2025240781A2 (en) 2024-05-15 2025-11-20 Werewolf Therapeutics, Inc. Modified antibodies and immunoglobulin formats

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1541435A (en) * 1975-02-04 1979-02-28 Searle & Co Immunological materials
NL8501219A (nl) 1985-04-29 1986-11-17 Stichting Vrienden Van De Stic Immunologisch complex, de bereiding en toepassing daarvan.
US4699784A (en) * 1986-02-25 1987-10-13 Center For Molecular Medicine & Immunology Tumoricidal methotrexate-antibody conjugate
US5770198A (en) 1988-05-18 1998-06-23 The Research Foundation Of The State Of New York Platelet-specific chimeric 7E3 immunoglobulin
US20030198956A1 (en) * 2002-02-21 2003-10-23 Lee Makowski Staged assembly of nanostructures
US20040018587A1 (en) * 1994-10-13 2004-01-29 Lee Makowski Nanostructures containing antibody assembly units
US5871945A (en) 1994-11-23 1999-02-16 Icos Corporation Modulators of anchoring protein function
US6261537B1 (en) 1996-10-28 2001-07-17 Nycomed Imaging As Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors
US6306393B1 (en) * 1997-03-24 2001-10-23 Immunomedics, Inc. Immunotherapy of B-cell malignancies using anti-CD22 antibodies
US7550143B2 (en) 2005-04-06 2009-06-23 Ibc Pharmaceuticals, Inc. Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
US7534866B2 (en) 2005-10-19 2009-05-19 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US7527787B2 (en) * 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
US6756039B1 (en) 1999-05-10 2004-06-29 The Regents Of The University Of California Self assembling proteins
US7666400B2 (en) 2005-04-06 2010-02-23 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US7060506B2 (en) 2000-01-31 2006-06-13 Cyclacel, Ltd. Compositions and methods for monitoring the modification of modification dependent binding partner polypeptides
US6524854B1 (en) * 2001-09-11 2003-02-25 Isis Pharmaceuticals, Inc. Antisense inhibition of PKA regulatory subunit RII alpha expression
CN100522999C (zh) * 2002-02-14 2009-08-05 免疫医疗公司 抗cd20抗体及其融合蛋白和使用方法
US8491896B2 (en) 2002-06-14 2013-07-23 Immunomedics, Inc. Anti-pancreatic cancer antibodies
US7591994B2 (en) * 2002-12-13 2009-09-22 Immunomedics, Inc. Camptothecin-binding moiety conjugates
US7432342B2 (en) * 2002-05-03 2008-10-07 Sequenom, Inc. Kinase anchor protein muteins, peptides thereof and related documents
US7906118B2 (en) 2005-04-06 2011-03-15 Ibc Pharmaceuticals, Inc. Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology
EP1618181B1 (en) * 2003-04-22 2014-10-15 IBC Pharmaceuticals Polyvalent protein complex
CA2523716C (en) * 2003-05-31 2014-11-25 Micromet Ag Human anti-human cd3 binding molecules
US20110064754A1 (en) 2005-03-03 2011-03-17 Center For Molecular Medicine And Immunology Immunoconjugates Comprising Poxvirus-Derived Peptides and Antibodies Against Antigen-Presenting Cells for Subunit-Based Poxvirus Vaccines
US8034352B2 (en) 2005-04-06 2011-10-11 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
US8551480B2 (en) 2004-02-13 2013-10-08 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US20110020273A1 (en) 2005-04-06 2011-01-27 Ibc Pharmaceuticals, Inc. Bispecific Immunocytokine Dock-and-Lock (DNL) Complexes and Therapeutic Use Thereof
US8003111B2 (en) 2005-04-06 2011-08-23 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo
US7901680B2 (en) 2005-10-19 2011-03-08 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
US8883160B2 (en) 2004-02-13 2014-11-11 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for therapeutic and diagnostic use
US8562988B2 (en) 2005-10-19 2013-10-22 Ibc Pharmaceuticals, Inc. Strategies for improved cancer vaccines
US8491914B2 (en) 2004-02-13 2013-07-23 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for delivery of interference RNA
EP3332808B1 (en) 2005-03-03 2020-09-09 Immunomedics Inc. Humanized l243 antibodies
AU2006232310B9 (en) * 2005-04-06 2011-07-21 Ibc Pharmaceuticals, Inc. Improved stably tethered structures of defined compositions with multiple functions or binding specificities
US9623115B2 (en) 2005-04-06 2017-04-18 Ibc Pharmaceuticals, Inc. Dock-and-Lock (DNL) Complexes for Disease Therapy
US8158129B2 (en) 2005-04-06 2012-04-17 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in vivo
US8481041B2 (en) 2005-04-06 2013-07-09 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US20120276100A1 (en) 2005-04-06 2012-11-01 Ibc Pharmaceuticals, Inc. Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity
US8475794B2 (en) 2005-04-06 2013-07-02 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases
US8349332B2 (en) 2005-04-06 2013-01-08 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
CN101484182B (zh) 2005-04-06 2014-06-11 Ibc药品公司 由同二聚体、同四聚体或二聚体的二聚体组成的稳定连接复合体的生产方法及用途
CN105709237A (zh) 2005-12-16 2016-06-29 Ibc 医药公司 基于免疫球蛋白的多价生物活性装配体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP1874824A4 *

Cited By (173)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9352036B2 (en) 2004-02-13 2016-05-31 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US8652484B2 (en) 2004-02-13 2014-02-18 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US8551480B2 (en) 2004-02-13 2013-10-08 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US9481878B2 (en) 2004-02-13 2016-11-01 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US8491914B2 (en) 2004-02-13 2013-07-23 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) complexes for delivery of interference RNA
US9492561B2 (en) 2004-02-13 2016-11-15 Ibc Pharmaceuticals, Inc. Dock-and-Lock (DNL) Complexes for delivery of interference RNA
US8435539B2 (en) 2004-02-13 2013-05-07 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US7878978B2 (en) 2004-03-18 2011-02-01 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Use of relaxin to increase arterial compliance
US8277817B2 (en) 2005-04-06 2012-10-02 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US8597659B2 (en) 2005-04-06 2013-12-03 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
US9359443B2 (en) 2005-04-06 2016-06-07 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 and anti-CD20 antibodies provides enhanced toxicity to B-cell diseases
US8906378B2 (en) 2005-04-06 2014-12-09 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, autoimmune disease and other diseases
US9931413B2 (en) 2005-04-06 2018-04-03 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
US8889835B2 (en) 2005-04-06 2014-11-18 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US8871216B2 (en) 2005-04-06 2014-10-28 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexvalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
US7906118B2 (en) 2005-04-06 2011-03-15 Ibc Pharmaceuticals, Inc. Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology
US9872920B2 (en) 2005-04-06 2018-01-23 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US7666400B2 (en) 2005-04-06 2010-02-23 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US7981398B2 (en) 2005-04-06 2011-07-19 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US8003111B2 (en) 2005-04-06 2011-08-23 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon pegylated site-specifically shows enhanced and prolonged efficacy in vivo
US9839689B2 (en) 2005-04-06 2017-12-12 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US9457100B2 (en) 2005-04-06 2016-10-04 Ibc Pharmaceuticals, Inc. PEGylation by the dock and lock (DNL) technique
US8034352B2 (en) 2005-04-06 2011-10-11 Ibc Pharmaceuticals, Inc. Tetrameric cytokines with improved biological activity
US8067006B2 (en) 2005-04-06 2011-11-29 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US8158129B2 (en) 2005-04-06 2012-04-17 Ibc Pharmaceuticals, Inc. Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in vivo
US9737617B2 (en) 2005-04-06 2017-08-22 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
US8481041B2 (en) 2005-04-06 2013-07-09 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US9707300B2 (en) 2005-04-06 2017-07-18 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US9248184B2 (en) 2005-04-06 2016-02-02 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy
US8475794B2 (en) 2005-04-06 2013-07-02 Ibc Pharmaceuticals, Inc. Combination therapy with anti-CD74 antibodies provides enhanced toxicity to malignancies, Autoimmune disease and other diseases
US9623115B2 (en) 2005-04-06 2017-04-18 Ibc Pharmaceuticals, Inc. Dock-and-Lock (DNL) Complexes for Disease Therapy
US8282934B2 (en) 2005-04-06 2012-10-09 Ibc Pharmaceuticals, Inc. Modular method to prepare tetrameric cytokines with improved pharmacokinetics by the dock-and-lock (DNL) technology
US9498542B2 (en) 2005-04-06 2016-11-22 Immunomedics, Inc. Tetrameric cytokines with improved biological activity
US8338140B2 (en) 2005-04-06 2012-12-25 Immunomedics, Inc. Polymeric carriers of therapeutic agents and recognition moieties for antibody-based targeting of disease sites
US8349332B2 (en) 2005-04-06 2013-01-08 Ibc Pharmaceuticals, Inc. Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
US9862770B2 (en) 2005-10-19 2018-01-09 Ibc Pharmaceuticals, Inc. Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US7901680B2 (en) 2005-10-19 2011-03-08 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
EP1937851A4 (en) * 2005-10-19 2010-08-25 Ibc Pharmaceuticals Inc METHOD AND COMPOSITIONS FOR PRODUCING BIOACTIVE GROUPS OF INCREASED COMPLEXITY AND THEIR USE
US8883162B2 (en) 2005-10-19 2014-11-11 Ibc Pharmaceuticals, Inc. Multivalent antibody complexes targeting IGF-1R show potent toxicity against solid tumors
US7906121B2 (en) 2005-10-19 2011-03-15 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US9457072B2 (en) 2005-10-19 2016-10-04 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
US8562988B2 (en) 2005-10-19 2013-10-22 Ibc Pharmaceuticals, Inc. Strategies for improved cancer vaccines
US10377829B2 (en) 2005-12-16 2019-08-13 Immunomedics, Inc. Isolated nucleic acid encoding an anti-IGF-1R antibody
US9441043B2 (en) 2005-12-16 2016-09-13 Immunomedics, Inc. Methods of treating cancer with antibodies that target the insulin-like growth factor type I receptor (IGF-1R)
US9751948B2 (en) 2005-12-16 2017-09-05 Immunomedics, Inc. Class of monospecific and bispecific humanized antibodies that target the insulin-like growth factor type I receptor (IGF-1R)
EP1959993A4 (en) * 2005-12-16 2010-06-30 Ibc Pharmaceuticals Inc POLYVALENTIC BIOACTIVE ARRANGEMENTS ON IMMUNOGLOBULIN BASIS
JP5096332B2 (ja) * 2006-06-27 2012-12-12 旭化成株式会社 生物学的液体処理用基材、生物学的液体処理用基材の製造方法、生物学的液体処理用デバイス、及び生物学的液体処理用デバイスの製造方法
WO2008001802A1 (en) 2006-06-27 2008-01-03 Asahi Kasei Kabushiki Kaisha Substrate for biological fluid treatment
US12016915B2 (en) 2007-02-02 2024-06-25 Baylor Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
US8728481B2 (en) 2007-02-02 2014-05-20 Baylor Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
US9453074B2 (en) 2007-02-02 2016-09-27 Baylor Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
US8236934B2 (en) 2007-02-02 2012-08-07 Baylore Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
EP2684889A3 (en) * 2007-02-02 2014-03-05 Baylor Research Institute Multivariable antigens complexed with targeting humanized monoclonal antibody
EP2114985A4 (en) * 2007-02-02 2010-09-22 Baylor Res Inst MULTIVARIABLE ANTIGEN COMPLEXES AND TARGET HUMANIZED MONOCLONAL ANTIBODY
US11173202B2 (en) 2007-02-02 2021-11-16 Baylor Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
US10279030B2 (en) 2007-02-02 2019-05-07 Baylor Research Institute Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
EP2156186A4 (en) * 2007-05-03 2010-11-03 Tethys Bioscience Inc BINDING REAGENTS WITH SMALL EPITOP BINDING MOLECULES
JP2008308423A (ja) * 2007-06-13 2008-12-25 Gunma Univ 両親媒性の高分子配位子によって安定化された高分子錯体および検査用組成物および医薬組成物
JP2017122087A (ja) * 2007-12-06 2017-07-13 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド インフルエンザウイルスに対する抗体およびその使用方法
US9951122B2 (en) 2007-12-06 2018-04-24 Dana-Farber Cancer Institute, Inc. Antibodies against influenza virus and methods of use thereof
JP2011506344A (ja) * 2007-12-06 2011-03-03 ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド インフルエンザウイルスに対する抗体およびその使用方法
US8034396B2 (en) 2008-04-01 2011-10-11 Tyco Healthcare Group Lp Bioadhesive composition formed using click chemistry
US10022427B2 (en) 2008-04-10 2018-07-17 Ibc Pharmaceuticals, Inc. Interferon lambda-antibody complexes
CN102066974B (zh) * 2008-04-30 2014-12-17 免疫医疗公司 用于蛋白、肽和其他分子的f-18标记的改进方法和组合物
CN102066974A (zh) * 2008-04-30 2011-05-18 免疫医疗公司 用于蛋白、肽和其他分子的f-18标记的改进方法和组合物
US9193780B2 (en) 2008-06-05 2015-11-24 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
US9834595B2 (en) 2008-06-05 2017-12-05 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
US11518799B2 (en) 2008-06-05 2022-12-06 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
US10550174B2 (en) 2008-06-05 2020-02-04 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
US20190077847A1 (en) 2008-06-05 2019-03-14 Ablynx N.V. Amino acid sequences directed against envelope proteins of a virus and polypeptides comprising the same for the treatment of viral diseases
WO2009150284A2 (es) 2008-06-13 2009-12-17 Proyecto De Biomedicina Cima, S.L. Conjugados de apo-a para la administración de compuestos biológicamente activos
EP2334705B1 (en) * 2008-09-26 2016-12-14 UCB Biopharma SPRL Biological products
WO2010063865A1 (es) 2008-12-03 2010-06-10 Proyecto De Biomedicina Cima, S.L. Uso de modulinas solubles en fenol para el desarrollo de vacunas
JP2012516683A (ja) * 2009-02-04 2012-07-26 ソンギュングヮン ユニバーシティ ファウンデーション フォー コーポレート コラボレーション 細胞内の伝達能が増加した低分子干渉ｒｎａ複合体
US8877170B2 (en) 2009-02-21 2014-11-04 Sofradim Production Medical device with inflammatory response-reducing coating
US8512728B2 (en) 2009-02-21 2013-08-20 Sofradim Production Method of forming a medical device on biological tissue
US8535477B2 (en) 2009-02-21 2013-09-17 Sofradim Production Medical devices incorporating functional adhesives
US9510810B2 (en) 2009-02-21 2016-12-06 Sofradim Production Medical devices incorporating functional adhesives
US8663689B2 (en) 2009-02-21 2014-03-04 Sofradim Production Functionalized adhesive medical gel
US8968733B2 (en) 2009-02-21 2015-03-03 Sofradim Production Functionalized surgical adhesives
US9272029B2 (en) 2009-03-26 2016-03-01 Ibc Pharmaceuticals, Inc. Interferon lambada-antibody complexes
EP2258398A1 (en) 2009-05-26 2010-12-08 Araclón Biotech, S. L. Albumin-amyloid peptide conjugates and uses thereof
US11028151B2 (en) 2009-06-05 2021-06-08 Ablynx N.V. Monovalent, bivalent and trivalent anti human respiratory syncytial virus (HRSV) nanobody constructs for the prevention and/or treatment of respiratory tract infections
US9803001B2 (en) 2009-06-05 2017-10-31 Ablynx N.V. Monovalent, bivalent and trivalent anti human respiratory syncytial virus (hRSV) nanobody constructs for the prevention and/or treatment of respiratory tract infections
WO2010139808A3 (en) * 2009-06-05 2011-02-24 Ablynx Nv Monovalent, bivalent and trivalent anti human respiratory syncytial virus (hrsv) nanobody constructs for the prevention and/or treatment of respiratory tract infections
US8945567B2 (en) 2009-06-05 2015-02-03 Ablynx N.V. Monovalent, bivalent and trivalent anti human respiratory syncytial virus (HRSV) nanobody constructs for the prevention and/or treatment of respiratory tract infections
WO2011029980A1 (es) 2009-09-11 2011-03-17 Proyecto De Biomedicina Cima, S.L. Composiciones terapéuticas para el tratamiento de enfermedades causadas por hpv
US9644022B2 (en) 2009-11-30 2017-05-09 Ablynx N.V. Amino acid sequences directed against human respiratory syncytial virus (HRSV) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections
WO2011101332A1 (en) 2010-02-16 2011-08-25 Proyecto De Biomedicina Cima, S.L. Compositions based on the fibronectin extracellular domain a for the treatment of melanoma
US9247931B2 (en) 2010-06-29 2016-02-02 Covidien Lp Microwave-powered reactor and method for in situ forming implants
US8865857B2 (en) 2010-07-01 2014-10-21 Sofradim Production Medical device with predefined activated cellular integration
WO2012123269A1 (en) 2011-03-11 2012-09-20 Proyecto De Biomedicina Cima, S.L. Immunogenic compositions and methods for their use
WO2012131139A1 (es) 2011-03-29 2012-10-04 Neo Virnatech, S.L. Composiciones de vacuna para enfermedades transmitidas por birnavirus
EP2505640A1 (en) 2011-03-29 2012-10-03 Neo Virnatech, S.L. Vaccine compositions for birnavirus-borne diseases
WO2013092509A1 (en) 2011-12-22 2013-06-27 Laboratorios Del Dr. Esteve, S.A. Inhibitors of sialoadhesin for the treatment of diseases caused by enveloped viruses
US9789130B2 (en) 2011-12-22 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Method for blocking HIV entry into dendritic cells by inhibiting sialoadhesin-sialyllactose binding interactions with gangliosides
EP2606897A1 (en) 2011-12-22 2013-06-26 Laboratorios Del. Dr. Esteve, S.A. Methods and compositions for the treatment of diseases caused by enveloped viruses
US9446123B2 (en) 2012-06-01 2016-09-20 Ibc Pharmaceuticals, Inc. Multimeric complexes with improved in vivo stability, pharmacokinetics and efficacy
US10308688B2 (en) 2012-08-14 2019-06-04 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US10239938B2 (en) 2012-08-14 2019-03-26 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US10662252B2 (en) 2012-08-14 2020-05-26 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to Trop-2 expressing cells
US9382329B2 (en) 2012-08-14 2016-07-05 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to Trop-2 expressing cells
US9670286B2 (en) 2012-08-14 2017-06-06 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to Trop-2 expressing cells
US9682143B2 (en) 2012-08-14 2017-06-20 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
US10245321B2 (en) 2012-08-14 2019-04-02 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
US9879088B2 (en) 2012-08-14 2018-01-30 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to Trop-2 expressing cells
US9315567B2 (en) 2012-08-14 2016-04-19 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US10111954B2 (en) 2012-08-14 2018-10-30 Ibc Pharmaceuticals, Inc. Combination therapy for inducing immune response to disease
US10183992B2 (en) 2012-08-14 2019-01-22 Ibc Pharmaceuticals, Inc. T-cell redirecting bispecific antibodies for treatment of disease
US9775928B2 (en) 2013-06-18 2017-10-03 Covidien Lp Adhesive barbed filament
US9932413B2 (en) 2013-11-01 2018-04-03 Ibc Pharmaceuticals, Inc. Murine, chimeric, humanized or human anti-IL-6 antibodies
US10385139B2 (en) 2013-11-01 2019-08-20 Ibc Pharmaceuticals, Inc. Murine, chimeric, humanized or human anti-TNF-alpha antibodies
US9416197B2 (en) 2013-11-01 2016-08-16 Ibc Pharmaceuticals, Inc. Bispecific antibodies that neutralize both TNF-α and IL-6: novel therapeutic agent for autoimmune disease
US11299528B2 (en) 2014-03-11 2022-04-12 D&D Pharmatech Inc. Long acting TRAIL receptor agonists for treatment of autoimmune diseases
US10993990B2 (en) 2014-05-16 2021-05-04 Baylor Research Institute Methods and compositions for treating autoimmune and inflammatory conditions
US11957734B2 (en) 2014-05-16 2024-04-16 Baylor Research Institute Methods and compositions for treating autoimmune and inflammatory conditions
US11820818B2 (en) 2014-05-29 2023-11-21 Macrogenics, Inc. Multi-chain polypeptide-containing tri-specific binding molecules
EP3954703A2 (en) 2014-05-29 2022-02-16 MacroGenics, Inc. Tri-specific binding molecules and methods of use thereof
US11697684B2 (en) 2014-05-29 2023-07-11 Macrogenics, Inc. Tri-specific binding molecules that specifically bind to multiple cancer antigens
US10633440B2 (en) 2014-05-29 2020-04-28 Macrogenics, Inc. Multi-chain polypeptide-containing tri-specific binding molecules that specifically bind to multiple cancer antigens
US10647768B2 (en) 2014-05-29 2020-05-12 Macrogenics, Inc. Multi-chain polypeptide-containing tri-specific binding molecules
WO2015184203A1 (en) 2014-05-29 2015-12-03 Macrogenics, Inc. Tri-specific binding molecules and methods of use thereof
US10501552B2 (en) 2015-01-26 2019-12-10 Macrogenics, Inc. Multivalent molecules comprising DR5-binding domains
US11717539B2 (en) 2015-02-18 2023-08-08 Enlivex Therapeutics RDO Ltd. Combination immune therapy and cytokine control therapy for cancer treatment
US11304976B2 (en) 2015-02-18 2022-04-19 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US12274714B2 (en) 2015-02-18 2025-04-15 Enlivex Therapeutics R&D Ltd Early apoptotic cells for use treating sepsis
US11000548B2 (en) 2015-02-18 2021-05-11 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11596652B2 (en) 2015-02-18 2023-03-07 Enlivex Therapeutics R&D Ltd Early apoptotic cells for use in treating sepsis
US11512289B2 (en) 2015-02-18 2022-11-29 Enlivex Therapeutics Rdo Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11497767B2 (en) 2015-02-18 2022-11-15 Enlivex Therapeutics R&D Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11318163B2 (en) 2015-02-18 2022-05-03 Enlivex Therapeutics Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11883429B2 (en) 2015-04-21 2024-01-30 Enlivex Therapeutics Rdo Ltd Therapeutic pooled blood apoptotic cell preparations and uses thereof
US10857181B2 (en) 2015-04-21 2020-12-08 Enlivex Therapeutics Ltd Therapeutic pooled blood apoptotic cell preparations and uses thereof
US9993547B2 (en) 2015-05-28 2018-06-12 Immunomedics, Inc. T20 constructs for anti-HIV (human immunodeficiency virus) therapy and/or vaccines
US9687547B2 (en) 2015-05-28 2017-06-27 Immunomedics, Inc. T20 constructs for anti-HIV (human immunodeficiency virus) therapy and/or vaccines
US11858991B2 (en) 2015-06-08 2024-01-02 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11072653B2 (en) 2015-06-08 2021-07-27 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
EP4303235A2 (en) 2015-06-08 2024-01-10 MacroGenics, Inc. Lag-3-binding moleculkes and methods of use thereof
EP3456346A1 (en) 2015-07-30 2019-03-20 MacroGenics, Inc. Pd-1 and lag-3 binding molecules and methods of use thereof
EP3981792A1 (en) 2015-07-30 2022-04-13 MacroGenics, Inc. Pd-1-binding molecules and methods of use thereof
WO2017019846A1 (en) 2015-07-30 2017-02-02 Macrogenics, Inc. Pd-1-binding molecules and methods use thereof
EP4450088A2 (en) 2015-07-30 2024-10-23 MacroGenics, Inc. Pd-1-binding molecules and methods of use thereof
US11623959B2 (en) 2015-07-30 2023-04-11 Macrogenics, Inc. PD-1-binding molecules and methods of use thereof
US10577422B2 (en) 2015-07-30 2020-03-03 Macrogenics, Inc. PD-1-binding molecules and methods of use thereof
US11174315B2 (en) 2015-10-08 2021-11-16 Macrogenics, Inc. Combination therapy for the treatment of cancer
US11840571B2 (en) 2015-12-14 2023-12-12 Macrogenics, Inc. Methods of using bispecific molecules having immunoreactivity with PD-1 and CTLA-4
WO2017106061A1 (en) 2015-12-14 2017-06-22 Macrogenics, Inc. Bispecific molecules having immunoreactivity with pd-1 and ctla-4, and methods of use thereof
US10954301B2 (en) 2015-12-14 2021-03-23 Macrogenics, Inc. Bispecific molecules having immunoreactivity with PD-1 and CTLA-4, and methods of use thereof
US11007251B2 (en) 2015-12-17 2021-05-18 The Johns Hopkins University Ameliorating systemic sclerosis with death receptor agonists
WO2017142928A1 (en) 2016-02-17 2017-08-24 Macrogenics, Inc. Ror1-binding molecules, and methods of use thereof
US11730761B2 (en) 2016-02-18 2023-08-22 Enlivex Therapeutics Rdo Ltd Combination immune therapy and cytokine control therapy for cancer treatment
US11084879B2 (en) 2016-04-07 2021-08-10 The Johns Hopkins University Compositions and methods for treating pancreatitis and pain with death receptor agonists
US11591400B2 (en) 2016-04-15 2023-02-28 Macrogenics, Inc. B7-H3 directed antibody drug conjugates
WO2017180813A1 (en) 2016-04-15 2017-10-19 Macrogenics, Inc. Novel b7-h3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
WO2018119166A1 (en) 2016-12-23 2018-06-28 Macrogenics, Inc. Adam9-binding molecules, and methods of use thereof
US11242402B2 (en) 2016-12-23 2022-02-08 Macrogenics, Inc. ADAM9-binding molecules, and methods of use thereof
EP4653464A2 (en) 2016-12-23 2025-11-26 MacroGenics, Inc. Adam9-binding molecules, and methods of use thereof
US11942149B2 (en) 2017-02-24 2024-03-26 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
EP4389226A2 (en) 2017-02-24 2024-06-26 MacroGenics, Inc. Bispecific binding molecules that are capable of binding cd137 and tumor antigens, and uses thereof
US11459394B2 (en) 2017-02-24 2022-10-04 Macrogenics, Inc. Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof
WO2018162450A1 (en) 2017-03-06 2018-09-13 Fundación Para La Investigación Médica Aplicada New inmunostimulatory compositions comprising an entity of cold inducible rna-binding protein with an antigen for the activation of dendritic cells
US11795226B2 (en) 2017-12-12 2023-10-24 Macrogenics, Inc. Bispecific CD16-binding molecules and their use in the treatment of disease
EP3752196A1 (en) 2018-02-15 2020-12-23 MacroGenics, Inc. Variant cd3-binding domains and their use in combination therapies for the treatment of disease
US10982210B2 (en) 2018-03-02 2021-04-20 Sixfold Bioscience Ltd. Compositions for delivery of cargo to cells
US12252582B2 (en) 2019-08-29 2025-03-18 University Of Delaware Biofunctional thiophene monomers and polymers thereof for electronic biomedical devices
US12435155B2 (en) 2020-02-21 2025-10-07 Macrogenics, Inc. CD137 binding molecules and uses thereof
US11357865B2 (en) 2020-04-27 2022-06-14 Sixfold Bioscience Ltd. Compositions containing nucleic acid nanoparticles with modular functionality
US12472267B2 (en) 2020-04-27 2025-11-18 Sixfold Bioscience Ltd. Compositions containing nucleic acid nanoparticles with modular functionality
US11767353B2 (en) 2020-06-05 2023-09-26 Theraly Fibrosis, Inc. Trail compositions with reduced immunogenicity
WO2022000136A1 (en) * 2020-06-28 2022-01-06 Dingfu Biotarget Co., Ltd. Methods and compositions for cancer treatment
WO2022010798A1 (en) 2020-07-06 2022-01-13 Kiromic BioPharma, Inc. Mesothelin isoform binding molecules and chimeric pd1 receptor molecules, cells containing the same and uses thereof
WO2022108627A1 (en) 2020-11-18 2022-05-27 Kiromic Biopharma, Inc.Kiromic Biopharma, Inc. Gamma-delta t cell manufacturing processes and chimeric pd1 receptor molecules

Also Published As

Publication number Publication date
US20060228300A1 (en) 2006-10-12
US20150050715A1 (en) 2015-02-19
US20110143417A1 (en) 2011-06-16
US7871622B2 (en) 2011-01-18
CA2604032A1 (en) 2006-10-12
US8906377B2 (en) 2014-12-09
CN101484182A (zh) 2009-07-15
WO2006107617A3 (en) 2008-08-14
US20090191225A1 (en) 2009-07-30
AU2006232920A1 (en) 2006-10-12
CA2604032C (en) 2017-08-22
AU2006232920B2 (en) 2011-09-29
JP5011277B2 (ja) 2012-08-29
CN101484182B (zh) 2014-06-11
US7521056B2 (en) 2009-04-21
JP2008538747A (ja) 2008-11-06
EP1874824A2 (en) 2008-01-09
EP1874824A4 (en) 2009-12-30
US9540435B2 (en) 2017-01-10

Similar Documents

Publication Publication Date Title
US9540618B2 (en) Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
AU2006232920B2 (en) Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
EP1959993B1 (en) Multivalent immunoglobulin-based bioactive assemblies
US8211440B2 (en) Multivalent immunoglobulin-based bioactive assemblies
US9169470B2 (en) Methods and compositions for generating bioactive assemblies of increased complexity and uses
WO2007046893A2 (en) Methods for generating bioactive assemblies and uses thereof
CA2604034A1 (en) Improved stably tethered structures of defined compositions with multiple functions or binding specificities
US20170121692A1 (en) Methods for Generating Stably Linked Complexes Composed of Homodimers, Homotetramers or Dimers of Dimers and Uses
EP2674440B1 (en) Multivalent immunoglobulin-based bioactive assemblies
HK1117761B (en) Multivalent immunoglobulin-based bioactive assemblies

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680019840.6

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 11633729

Country of ref document: US

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 11633729

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2006232920

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2604032

Country of ref document: CA

Ref document number: 2008505356

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 7673/DELNP/2007

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: DZP2007000659

Country of ref document: DZ

ENP Entry into the national phase

Ref document number: 2006232920

Country of ref document: AU

Date of ref document: 20060324

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 2006748646

Country of ref document: EP