EP1483293A2 - Verwendung einer an cd28 bindenden wirksubstanz zur herstellung einer pharmazeutischen zusammensetzung - Google Patents
Verwendung einer an cd28 bindenden wirksubstanz zur herstellung einer pharmazeutischen zusammensetzungInfo
- Publication number
- EP1483293A2 EP1483293A2 EP03717153A EP03717153A EP1483293A2 EP 1483293 A2 EP1483293 A2 EP 1483293A2 EP 03717153 A EP03717153 A EP 03717153A EP 03717153 A EP03717153 A EP 03717153A EP 1483293 A2 EP1483293 A2 EP 1483293A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cells
- mab
- superagonistic
- specific
- regulatory
- 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
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 239000013543 active substance Substances 0.000 title claims description 17
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims abstract description 97
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims abstract description 96
- 230000002483 superagonistic effect Effects 0.000 claims abstract description 60
- 210000003289 regulatory T cell Anatomy 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 64
- 210000004027 cell Anatomy 0.000 claims description 63
- 241000282414 Homo sapiens Species 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- 230000000638 stimulation Effects 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 230000003053 immunization Effects 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 230000036961 partial effect Effects 0.000 claims description 9
- 230000008921 facial expression Effects 0.000 claims description 8
- 210000004408 hybridoma Anatomy 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 4
- 238000003556 assay Methods 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 239000012228 culture supernatant Substances 0.000 claims description 3
- 206010061811 demyelinating polyneuropathy Diseases 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 238000000159 protein binding assay Methods 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000012216 screening Methods 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 210000001124 body fluid Anatomy 0.000 claims 3
- 239000010839 body fluid Substances 0.000 claims 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 210000000130 stem cell Anatomy 0.000 claims 1
- 230000006698 induction Effects 0.000 abstract description 8
- 230000003278 mimic effect Effects 0.000 abstract 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 38
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 38
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 38
- 241000700159 Rattus Species 0.000 description 34
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- 230000004940 costimulation Effects 0.000 description 18
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- 230000035755 proliferation Effects 0.000 description 13
- 150000001413 amino acids Chemical group 0.000 description 12
- 108091008874 T cell receptors Proteins 0.000 description 11
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 11
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 10
- 230000000139 costimulatory effect Effects 0.000 description 9
- 238000002649 immunization Methods 0.000 description 9
- 102000006306 Antigen Receptors Human genes 0.000 description 7
- 108010083359 Antigen Receptors Proteins 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 230000032823 cell division Effects 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 239000007850 fluorescent dye Substances 0.000 description 4
- 150000007523 nucleic acids Chemical group 0.000 description 4
- 230000000284 resting effect Effects 0.000 description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 229940045513 CTLA4 antagonist Drugs 0.000 description 3
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 3
- 102000006386 Myelin Proteins Human genes 0.000 description 3
- 108010083674 Myelin Proteins Proteins 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000004073 interleukin-2 production Effects 0.000 description 3
- 210000005087 mononuclear cell Anatomy 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 206010057645 Chronic Inflammatory Demyelinating Polyradiculoneuropathy Diseases 0.000 description 2
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 210000004970 cd4 cell Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 210000005012 myelin Anatomy 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 1
- 208000037187 Autoimmune Experimental Neuritis Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108700031361 Brachyury Proteins 0.000 description 1
- 102000049320 CD36 Human genes 0.000 description 1
- 108010045374 CD36 Antigens Proteins 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 102220493630 HLA class II histocompatibility antigen, DRB1 beta chain_F60V_mutation Human genes 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000037979 autoimmune inflammatory disease Diseases 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 210000004754 hybrid cell Anatomy 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000010212 intracellular staining Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000007885 magnetic separation Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102200162626 rs1131692042 Human genes 0.000 description 1
- 102220162519 rs144164853 Human genes 0.000 description 1
- 102220166652 rs886048559 Human genes 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
Definitions
- Tumor cell have arisen.
- the C'-D loop of CD28 comprises amino acids 52 to 66 of the above CD28 sequence (for numbering see also Ostrov, D.A., et al.; Science (2000), 290: 816-819).
- the term “C'-D loop” should also be understood to mean any partial sequences from this.
- a loop or a binding site arranged in it is freely accessible if none for a defined binding partner for the binding site in the loop steric hindrance due to sequences or molecules connected to the loop.
- Regulatory T cells are CD4 + T cells which, when mixed with naive CD4 + T cells, inhibit their activation. These include in particular CD4 + CD25 + T cells. Another feature of regulatory T cells is a low expression of the high molecular isoforms of CD45 (human: RA) compared to other T cells. The constitutive expression of CD152 is typical for regulatory T cells.
- CD4 + CD8-SP thymocytes are one of the major sources of regulatory T cells.
- Homology denotes an at least 70%, preferably at least 80%, most preferably at least 90% sequence identity at the protein level, a homologous protein or peptide binding a defined binding partner with at least the same affinity. Sequence variations can include deletions, substitutions, insertions, and elongations.
- a facial expression compound is a natural or synthetic chemical structure that behaves like a defined mAb in a defined binding assay, which the facial expression compound mimicizes.
- the term mAb also includes structures which consist exclusively of the Fab fragment. It is also possible to use only the variable region, the heavy chain fragment being connected to the light chain fragment in a suitable manner, for example also by means of synthetic bridge molecules, in such a way that the binding regions of the chains form the antibody epitope.
- the term antibody also includes (possibly complete) chimeric and humanized antibodies.
- Superagonistic stimulation of the proliferation of CD 28 specific T cells means that no costimulation, i.e. no other binding event besides binding a mAb or a mimicriver connection to CD28 is required to stimulate or inhibit proliferation.
- the activation of resting T cells for proliferation and functional differentiation first requires the occupation of two surface structures, so-called receptors: 1. the antigen receptor, which has a different specificity from cell to cell and for recognition of antigens, for example viral fission products, is necessary; and 2. the CD28 molecule which is equally expressed on all resting T cells, with the exception of a subset of the CD8 T cells of humans, which naturally binds to ligands on the surface of other cells of the immune system.
- TH1 and TH2 cells are CD4-expressing T cells.
- TH1 cells are also called pro-inflammatory T-helper cells
- TH2 cells "support. The. Activation of B cells and. Secrete the cytokines IL-4, IL-5 and IL-10. The differentiation. From CD4 T cells to the above • functionally different subgroups is not only achieved by
- CD28 deficient mice show normal TH1 but reduced TH2 dependent responses and the cytokine profile of TCR-transgenic CD4 cells is determined by CD28 ligation
- T cells are important in autoimmune reactions. For example, in experimental animal models of multiple sclerosis, type I diabetes and inflammatory bowel diseases the ability of these cells
- GBS Guillain-Barre syndrome
- CDP chronic demyelinating polyneuropathy
- CDP 10-20 per 100,000 people.
- the invention teaches the use of a CD28-specific superagonistic monoclonal antibody (mAb) or one
- Facial expression compound for this purpose, for the production of a pharmaceutical composition for induction and / or proliferation of regulatory T cells.
- the invention is based on the knowledge that the active substances used according to the invention appear to be a very good means of treating Guillian-Barre syndrome and / or chronically demyelinating polyneuropathy and other autoimmune-related ones
- the invention therefore further teaches the use according to the invention for the treatment of these diseases.
- mAb can be a mAb, which is available with hybridoma cells as deposited under the DSM numbers DSM ACC2531 (mAb: 9D7 or 9D7G3H11) or DSM ACC2530 (mAb: 5th ILA or 5.11A1C2H3).
- the mAb can be one or more of the sequences SEQ ID 9, 11, 13 and / or
- SEQ ID 13 shows the nucleic acid sequence of the variable region of the heavy chain of a mAb 5.11A according to the invention.
- SEQ ID 14 shows the peptide encoded thereby.
- SEQ ID 15 shows the nucleic acid sequence of the variable region of the light chain of this mAb.
- SEQ ID 16 is the peptide encoded thereby.
- SEQ-ID 9 shows the nucleic acid sequence of the variable region of the light chain of a mAb 9D7 according to the invention.
- SEQ-ID 10 shows the peptide encoded thereby.
- SEQ ID 11 shows the nucleic acid sequence of the variable region of the heavy chain of this mAb.
- SEQ-ID 12 is the peptide encoded thereby. Show SEQ ID 18 and 19
- the invention also relates to curative methods in which a disease based on low regulator T cell numbers or high T lymphocyte infiltration in organs or tissues, for example a person suffering from GBS and / or CDP, an inventive pharmaceutical composition in pharmacologically effective dosage and is administered in galenic preparation suitable for administration.
- a disease based on low regulator T cell numbers or high T lymphocyte infiltration in organs or tissues for example a person suffering from GBS and / or CDP
- an inventive pharmaceutical composition in pharmacologically effective dosage and is administered in galenic preparation suitable for administration.
- Fig. 4 Binding of different human CD28 specific mAb to CD28 (a) and costimulatory (b) and • superagonistic (c) activity of the mAb of Figure 4a,
- Fig. 5 Binding experiments which prove that superagonistic mAb bind specifically to 'the C'-D loop
- Fig. 11 Induction of CD4 + CD25 + proliferation
- Fig. 15 Disease course of the active EAN under
- Fig. 17 Treatment corresponding to Fig. 15, but with a different treatment plan
- Proliferation of the indicator cells with and without stimulation (CD3 / anti CD28), B: suppression of the proloferation of the indicator cells in the presence of expanded CD4 + CD25 +++ T cells.
- FIG. 1 shows the stimulation of freshly isolated T lymphocytes in the form of a 3H-thymidine incorporation in the rat.
- the methodology corresponds to that described in reference W098 / 54225, to which full reference is made here and below, and the contents of which are hereby incorporated into the present text.
- the costimulation is shown in FIG. 1 a, ie T-cell receptor (TCR) -specific mAbs were bound to the plastic surface in all wells. In the absence of costimulation, the negative control (top row) shows no installation. Costimulation is then given in soluble form by the addition of CD28-specific mAb. The entire range of CD28-specific mAb shown was used.
- This series of different CD28-specific mAbs originates from an approach of immunization and production of hybridoma cell lines already described in WO98 / 54225.
- the culture supernatants contained enough CD28-specific mAb for saturating binding to 2 ⁇ 10 5 T cells. It can be seen from FIG. 1 a that all of these mAb are capable of activating in a costimulating manner, ie in the presence of the anti-TCR mAb the thymidine incorporation to stimulate. The stimulation in the absence of TCR-specific mAb is shown in FIG. 1b.
- This experiment was also carried out as described in reference W098 / 54225. It can be seen that only two mAbs are able to stimulate T lymphocytes in the absence of a TCR signal. So these mAb have superagonistic activity.
- CD28-specific mAbs bind to different areas of the CD28 molecule.
- the mAbs were prepared by immunizing mice with rat CD28; therefore, as expected, they all do not react with mouse CD28 (not shown). Since the mAb can therefore only recognize those regions of the rat CD28 molecule which differ from that of the mouse, a sequence comparison between CD28 of the mouse and the rat was first carried out (see FIG. 2, upper part). The differences between the two species are highlighted. The one-letter code was used to name the amino acids. JJ319 was used as a prototype for a conventional rat CD28-specific mAb, and JJ316 was used for a superagonistic mAb (see W098 / 54225).
- FIG. 3 The mapping of the binding is shown in FIG.
- Expression plasmids were constructed in which part of the extracellular domain of CD28 originates from the mouse and another part from the rat. This is represented symbolically by bars and dashes; to the right is shown the binding of mAb JJ316 and JJ319 to mouse fibroblasts (L929 cells) that had been transfected with these expression plasmids.
- Fig. 3 m / r and r / m 1-37
- the binding of both antibodies to the "right" half of the sequence is mapped: both bind if this originates from the rat; No binding takes place in the reverse construct (rm CD28 1-37, left rat, right mouse).
- the third line (m / r CD28 1-66) shows that JJ316 no longer binds, while the part of the rat sequence ("right") that is still available is still sufficient for recognition by JJ319. Accordingly, the two mAb recognize different epitopes on the CD28 molecule, and the binding of the superagonist JJ316 must therefore be sought in the region that originated from the rat in the first line construct, but not in the third line construct.
- the clear candidate for this is the area encased in FIG. 2.
- mice were immunized with human CD28-transfected A20 / J mouse B lymphoma cells (see WO98 / 54225) and additionally before the fusion with commercially available human CD28-FC
- Fusion protein boosted (purchased from R and D Systems).
- approximately 20 were identified from several thousand cell lines that produce human CD28-specific mAbs (binding to mouse L929 cells that express human CD28 but not to untransfected L929 cells), analogously to the screen in reference W098 / 54,225th Two of these showed the desired superagonistic activity (9D7 and 5.11A), while all new mAbs have conventional costimulatory activity.
- the two superagonistic mAbs are described in particular below.
- the newly generated mAb 7.3B6 is used as an example of a conventional human CD28-specific mAb.
- FIG. 4a shows that the preparations used for the three new mAbs bind to human T lymphocytes comparatively well and also with a comparable titer.
- An experiment is shown in which freshly isolated mononuclear cells from human blood (so-called PBMC) were first treated with various dilution levels of the mAb used on ice; then it was washed and the bound mAb visualized by a fluorescent dye-labeled secondary antibody that specifically recognizes the bound mouse mAb.
- PBMC mononuclear cells from human blood
- the binding of the titrated mAb could be determined selectively for CD4 T lymphocytes by electronic gating.
- MFI indicates the average fluorescence intensity, which is a measure of the amount of bound CD28-specific mAb.
- concentrations represent 3-fold dilutions of a standardized 'starting preparation. It is quite normal that the highest concentration gives a weaker signal than the following titration steps in this test; this has to do with the avidity (bivalent binding) of mAb and plays no role in the contexts discussed here.
- Figures 4b and c compare the ability of superagonistic human CD28-specific mAb with that of conventional CD28-specific mAb - in the presence and absence of a ' TCR signal - to stimulate freshly isolated human T cells to grow. A 3H-thymidine incorporation is again shown, as described above for the rat.
- the wells were coated with a mAb that reacts with the human TCR / CD3 complex. So costimulation was measured. It can be seen that there is no proliferation without costimulation with one of the mAbs (negative control), but all three antibodies are able to stimulate cell division.
- Figure 4c was worked in the absence of a TCR / CD3 specific mAb. Only antibodies 9D7 and 5. ILA were able to stimulate superagonistically.
- FIG. 1 A three-dimensional model of the CD28 molecule is shown in FIG. The newly identified binding region is highlighted. It corresponds to the encased sequence in Figure 2.
- the extracellular The domain of CD28 belongs structurally to the so-called immunoglobulin superfamily, which is characterized by two ß-leaflets one above the other as the basic structure. These tapes are labeled according to a pattern given in the literature. It is important for the representation shown here that the region identified as an epitope for superagonistic CD28-specific mAbs in rats and mice is referred to as "C'-D loop".
- mAb with specificity for the C'-D loop of the CD28 molecule have superagonistic activity, that is to say can be used in the sense of literature reference W098 / 54225 for activating T lymphocytes.
- the superagonistic activity of the C'-D loop of specific mAbs in rats and humans shows that it is not the sequence of the epitope that matters, but its location or shape.
- FIG. 7 shows that there is no IL-2 production without stimulation (negative control). Stimulation with a T cell receptor-specific mAb induces IL-2 production (positive control).
- FIG. 7 shows that there is no IL-2 production without stimulation (negative control). Stimulation with a T cell receptor-specific mAb induces IL-2 production (positive control).
- FIG. 7a shows the results when using the rat superagonistic mAb JJ316
- FIG. 7b shows results for the mAb 5.11A specific for human C'-D loop.
- the stimulation is not carried out by means of "conventional" CD28-specific mAb, since these not only do not bind to the C'-D loop, but cannot recognize the construct at all, because they are used for rat or are human-specific sequences that are not included in the construct.
- FIG. 9 shows dot plots in which each measured cell is represented by a point.
- the phenotypic characterization of the regulatory T cells was carried out by combining the cell surface molecules CD4 and CD25. For this purpose the cell suspensions are incubated with corresponding fluorescent dye labeled monoclonal antibodies to CD4 or CD25 •, washed and examined these antibodies in a fürflußzytophotometer for binding. The results shown were obtained three days after ip injection of a costimulatory (Fig. 9a, JJ319) or superagonistic CD28 specific mAb (Fig. 9b, JJ316).
- CD4 T cells In the case of JJ319, about 7% of the CD4 T cells are also CD25 positive (4 / (50 + 4)), which corresponds to results not shown in untreated animals. In contrast, after treatment with JJ316, approximately 20% are CD4 + CD25 + (10 / (10 + 40)). In addition, the level of CD25 expression is much higher than in the control animal. Such a high level is characteristic of regulatory T cells.
- FIG. 10 shows a phenotypic characterization in the form of a histogram.
- the marker CD45RC was detected in FIGS. 10a to 10c, a high molecular isoform of the CD45 molecule, which is strong on naive CD4 T cells but low on stimulated CD4 T cells is expressed. Low expression is typical of regulatory T cells.
- 10a shows that CD4 + CD25 cells from untreated animals mostly express CD45RC strongly. In contrast, in the case of CD4 + CD25 + cells from untreated animals, strong ones are found
- FIG. 10b In the case of treatment with the superagonistic CD28-specific mAb (FIG. 10c), the down-regulation of CD45CD45RC is much more pronounced than in the case of FIG. 10b.
- FIGS. 10d to 10e the CD152 (CTLA-4) constitutively expressed by regulatory T cells is detected by staining. This staining has to be carried out due to the intracellular localization of CD152 after permeabilization of fixed cells and is therefore associated with an unspecific background. To check this, a so-called isotype control was carried out, ie an intracellular staining was carried out with a mAb of the same immunoglobulin class, which, however, cannot recognize anything specifically.
- the specific CD152 detection results as a shift of the CD152 histogram compared to the isotype control histogram. There is no shift in FIG. 10d and consequently no CD152 expression in the CD4 + CD25 cells.
- FIGS. 10e In the untreated CD4 + CD25 + cells, a slight shift (FIG. 10e) and in the JJ316 (superagonistic CD28-specific mAb) treated cells, a stronger shift can be seen in accordance with the results of FIGS. 10a to 10c.
- FIGS. 9 and 10 show phenotypically how regulatory T cells can be identified and that superagonistic CD28-specific mAb preferentially increase or induce regulatory CD4 T cells in vivo.
- CD4 + CD25 + cells were isolated by electronic cell sorting either from untreated rats (FIG. 11a) or from rats treated with JJ316 (FIG. 11b) and cultured in 96 well plates according to the prior art. Cell proliferation was measured by 3H thymidine incorporation between days 2 and 3 of cultivation.
- “(-)” means no stimulation
- costimulation means stimulation with a non-superagonistic CD28 specific mAb (JJ319) as well as with the TCR specific R73
- JJ316 shows the superagonistic stimulation.
- Both Figures 11a and 11b show that regulatory T cells react poorly to costimulation, but well to stimulation with a superagonistic CD28 specific mAb. Stimulation with mAb used according to the invention thus shows a considerable increase in regulatory T cells even in cell culture.
- FIG. 13 shows a representation corresponding to FIG. 10f, but after in vitro stimulation with superagonistic CD28-specific mAbs (JJ316). An even more detectable CD152 expression can be seen.
- FIG. 13 shows the inhibitory function of regulatory T cells on CD4 + CD25 T cells, which serve as indicator cells for the suppressive effect.
- CD4 + CD25- T cells were used for costimulation (R73 + JJ319).
- the 3H thymidine incorporation was measured between days 2 and 3 of the cultivation.
- CD25 + means electronically sorted CD4 + CD25 + T cells from animals treated three days earlier with superagonistic CD28-specific mAb (JJ316).
- CD25- stands for the indicator cells.
- CD25 + / CD25- in Fig. 13a means that both cell populations were mixed together in equal parts. It can be seen that the CD25 + cells do not respond to costimulation with proliferation. In addition, the proliferation of indicator cells is suppressed.
- 13b shows a titration of the regulatory T cells by mixing them with indicator cells in different proportions. It can be seen that suppression can still be observed even when the ratio of regulatory to indicator cells is 1:16. This shows the high effectiveness of the regulatory cells stimulated with mAb used according to the invention.
- FIG. 14 shows a comparison of the reactions of human CD4 + CD25 T cells (naive cells) to CD4 + CD25 + T cells (regulatory cells) in response to costimulation (anti-CD3 + conventional anti-CD28 mAb) or to human specific superagonistic CD28 specific mAb (9D7 and 5.11A).
- the experiments correspond to those described above for the rat. Starting from the left, the first three groups show unstimulated controls (no 3H thymidine incorporation). These are the entire CD4 + T cells, then the CD25 fraction obtained by sorting and finally the CD25 + fraction obtained by sorting, "med” means medium. This is followed by two groups, in which was stimulated superagonistically (9D7 and 5.11A).
- the regulatory T cells react better to the stimulation with superagonistic CD28-specific mAbs compared to the total population of the CD4 + cells and their CD25 fraction.
- the last group of three shows the results of conventional costimulation. In contrast, the reaction of the unseparated T cells and the CD25 fraction is rather better.
- FIG. 15 shows the course of the disease of the active EAN under treatment with various mAbs.
- 7-8 week old female LEW rats available from Charles River Laboratories (Sulzfeld, Germany) were used.
- the animals were immunized with a synthetic peptide which corresponds to a part of the myelin protein P2 which surrounds peripheral nerve fibers (amino acids 53-78 of the bovine P2 protein, 50 ⁇ l of a 0.5mg / ml solution, inoculation in the balls of the feet).
- peripheral nerve fibers amino acids 53-78 of the bovine P2 protein, 50 ⁇ l of a 0.5mg / ml solution, inoculation in the balls of the feet.
- progressive paralysis develops, which can be quantified according to standardized scoring (King et al., Exp Neurol, 87: 9-19 (1985).
- Figure 15a shows preventive therapy with superagonistic CD28-specific mAbs (JJ316 15b Treatment with conventional mAb (JJ319)
- the application was carried out ip in lmg / animal doses either on the day of the P2 immunization (DO), on day 12 (D12), ie after the onset of symptoms, or on both days.
- the different groups included 3 to 6 animals.
- a comparison of FIGS. 15a and 15b shows that treatment with superagonistic CD28-specific mAb is significantly more effective than treatment with conventional mAb.
- FIG. 16 shows results corresponding to FIG. 15, but with a prophylactic treatment, d-7 being treatment 7 days before the immunization, d-21 21 days before the immunization. It can be seen that a resistant status can be achieved by increasing regulatory T cells when treated within a week before the immunization, but not when treated 3 weeks before the immunization.
- FIG. 17 is based on a procedure as in FIG. 15, but treatment with JJ316 on day 0 and 4.
- FIG. 17a shows the course of the disease in accordance with the illustration in FIG. 15a.
- FIG. 17b shows electrophysical properties, namely the speed of the conduction as a direct clinical parameter for the damage to the sciatic nerve.
- the measurements were carried out according to the literature Adlkofer et al. Nat Genet, 11: 274-280 (1995) and Heininger et al. , Ann Neurol, 19: 44-49 (1986).
- the pathological findings can be seen in the control groups, particularly in the prolongation of the N1 and F latencies (see days 0 and 12, open symbols).
- FIG. 18 shows results of a therapy of passive or adoptive transfer EAN (AT-EAN). This is not induced by immunization with the nerve antigen, as described above, but rather an intravenous injection of an autoreactive CD4 + T cell clone with specificity for the P2 myelin antigen (8xl0 ⁇ 6, cell line G7) according to the Stienekemeier et al. , Brain, 122: 523-535 (1999).
- FIG. 18a shows the course of the disease in a control group, in the case of treatment with JJ316 on day 1 (dl) and in the case of treatment on day 3 (d3). It is remarkable that even after the onset of the symptoms of the disease, ie treatment on day 3, the disease can be stopped.
- CD4 + CD25 +++ T cells expanded by means of monoclonal antibodies according to the invention also have their functional properties, e.g. the suppression of the proliferation of "conventional" T cells.
- the CD4 + T cells were purified from human peripheral mononuclear cells (PBMC) by means of magnetic separation
- CD8 +, CDllb +, CD16 +, CD19 +, CD36 + and CD56 + cells were then loaded with a CD25-specific antibody and subsequently a PE-conjugated secondary antibody, sorted into CD4 + CD25 +++ and CD4 + CD25-T cells (see FIG. 19) and after addition of monoclonal antibodies according to the invention coupled to Dyna-beads ( hulG4) and interleukin 2 (IL-2) cultivated (day 0). On day 5, the expanded cells were stained with anti-CD4 and anti CD-25 on the cell surface, and intracellularly with anti-CTLA-4 and Ki-67.
- hulG4 Dyna-beads
- IL-2 interleukin 2
- expanded CD4 + CD25 +++ or CD4 + CD25-T cells were mixed with the CFSE-labeled indicator cells in a ratio of 1: 1 or 1: 5 and co-cultivated (stimulation with anti-CD3 mAb, clone HIT3a, final concentration 0.1 ⁇ g / ml, and anti-CD-28 mAb, clone CD28.2, final concentration 0.05 ⁇ g / ml).
- Figure 22b shows that the number of cell divisions in the indicator cells was greatly reduced by the presence of the expanded CD4 + CD25 +++ T cells, while the CD4 + CD25-T cells showed only a slight effect.
Landscapes
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Cell Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Developmental Biology & Embryology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10212108A DE10212108A1 (de) | 2002-03-13 | 2002-03-13 | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer pharmazeutischen Zusammensetzung |
DE10212108 | 2002-03-13 | ||
PCT/DE2003/000890 WO2003078468A2 (de) | 2002-03-13 | 2003-03-13 | Verwendung einer an cd28 bindenden wirksubstanz zur herstellung einer pharmazeutischen zusammensetzung |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1483293A2 true EP1483293A2 (de) | 2004-12-08 |
Family
ID=27797912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03717153A Ceased EP1483293A2 (de) | 2002-03-13 | 2003-03-13 | Verwendung einer an cd28 bindenden wirksubstanz zur herstellung einer pharmazeutischen zusammensetzung |
Country Status (5)
Country | Link |
---|---|
US (5) | US20040092718A1 (de) |
EP (1) | EP1483293A2 (de) |
AU (1) | AU2003221604A1 (de) |
DE (1) | DE10212108A1 (de) |
WO (1) | WO2003078468A2 (de) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7794710B2 (en) * | 2001-04-20 | 2010-09-14 | Mayo Foundation For Medical Education And Research | Methods of enhancing T cell responsiveness |
EP1460088A1 (de) * | 2003-03-21 | 2004-09-22 | Biotest AG | Humanisierter Antikörper gegen CD4 mit immunsuppressiven Merkmalen |
DE10345008A1 (de) * | 2003-09-22 | 2005-04-28 | Tegenero Ag | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer pharmazeutischen Zusammensetzung mit dosisabhängiger Wirkung |
EP1600164A3 (de) * | 2003-09-22 | 2006-05-17 | TeGenero AG | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer Pharmazeutischen Zusammensetzung mit dosisabhängiger Wirkung |
DE10352900A1 (de) * | 2003-11-11 | 2005-06-16 | Tegenero Ag | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von B-CLL |
GB0400440D0 (en) | 2004-01-09 | 2004-02-11 | Isis Innovation | Receptor modulators |
PT2171060E (pt) * | 2004-11-11 | 2013-11-18 | Theramab Llc | Anticorpo anti-cd28 superagonista |
US7585960B2 (en) | 2005-05-11 | 2009-09-08 | Theramab Gmbh | Nucleic acids encoding superagonistic anti-CD28 antibodies |
EP2262838B1 (de) * | 2008-03-13 | 2016-04-13 | Biotest AG | Mittel zur behandlung einer erkrankung |
SG190627A1 (en) * | 2008-03-13 | 2013-06-28 | Biotest Ag | Agent for treating disease |
MX2010010028A (es) * | 2008-03-13 | 2011-08-17 | Biotest Ag | Agente para tratar enfermedad. |
DK2341937T3 (en) * | 2008-09-29 | 2015-02-09 | Biotest Ag | Composition for the treatment of a disease |
GB0920944D0 (en) | 2009-11-30 | 2010-01-13 | Biotest Ag | Agents for treating disease |
US8609625B2 (en) * | 2011-06-24 | 2013-12-17 | Taipei Veterans General Hospital | Method for enhancing immune response in the treatment of infectious and malignant diseases |
US20180206726A1 (en) | 2016-12-07 | 2018-07-26 | Progenity Inc. | Gastrointestinal tract detection methods, devices and systems |
US20210138213A1 (en) | 2017-03-30 | 2021-05-13 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immune modulatory agent released using an ingestible device |
CN112638375A (zh) | 2018-06-15 | 2021-04-09 | 旗舰创业创新五公司 | 通过后细胞信号传导因子的调节来增加免疫活性 |
US20230009902A1 (en) | 2018-06-20 | 2023-01-12 | Progenity, Inc. | Treatment of a disease or condition in a tissue orginating from the endoderm |
WO2019246312A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
EP3883635A1 (de) | 2018-11-19 | 2021-09-29 | Progenity, Inc. | Verfahren und vorrichtungen zur behandlung einer krankheit mit biotherapeutika |
MA55805A (fr) | 2019-05-03 | 2022-03-09 | Flagship Pioneering Innovations V Inc | Métodes de modulation de l'activité immunitaire |
CN115666704A (zh) | 2019-12-13 | 2023-01-31 | 比奥拉治疗股份有限公司 | 用于将治疗剂递送至胃肠道的可摄取装置 |
WO2021127217A1 (en) | 2019-12-17 | 2021-06-24 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
US20230355804A1 (en) | 2020-06-29 | 2023-11-09 | Flagship Pioneering Innovations V, Inc. | Viruses engineered to promote thanotransmission and their use in treating cancer |
KR102607909B1 (ko) | 2020-08-19 | 2023-12-01 | 젠코어 인코포레이티드 | 항-cd28 조성물 |
AU2022246895A1 (en) | 2021-03-31 | 2023-10-19 | Flagship Pioneering Innovations V, Inc. | Thanotransmission polypeptides and their use in treating cancer |
EP4363059A1 (de) | 2021-06-29 | 2024-05-08 | Flagship Pioneering Innovations V, Inc. | Zur förderung der apo-übertragung manipulierte immunzellen und verwendungen davon |
US20240059786A1 (en) * | 2022-02-24 | 2024-02-22 | Xencor, Inc. | Anti-cd28 x anti-trop2 antibodies |
US20240174732A1 (en) | 2022-10-05 | 2024-05-30 | Flagship Pioneering Innovations V, Inc. | Nucleic acid molecules encoding trif and additional polypeptides and their use in treating cancer |
WO2024151687A1 (en) | 2023-01-09 | 2024-07-18 | Flagship Pioneering Innovations V, Inc. | Genetic switches and their use in treating cancer |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5025825A (en) * | 1990-06-15 | 1991-06-25 | Moen Incorporated | Riser spout diverter assembly |
US5257824A (en) * | 1991-12-30 | 1993-11-02 | Eggen Harald I | Extender for a plumbing mount with spring loaded sealing piston |
US5591629A (en) * | 1994-04-29 | 1997-01-07 | Mayo Foundation For Medical Education & Research | Monoclonal antibodies which promote central nervous system remyelination |
CA2194814A1 (en) * | 1997-01-10 | 1998-07-10 | Terry L. Delovitch | Stimulation of protective t cells to prevent autoimmune disease |
DE19722888A1 (de) * | 1997-05-28 | 1998-12-03 | Thomas Prof Dr Huenig | Human-CD28 spezifische monoklonale Antikörper zur antigenunspezifischen Aktivierung von T-Lymphozyten |
IL151287A0 (en) * | 2000-02-24 | 2003-04-10 | Xcyte Therapies Inc | A method for stimulation and concentrating cells |
AU2002357427A1 (en) * | 2001-12-04 | 2003-06-17 | Tegenero Ag | Peptide or protein containing a c'-d loop of the cd28 receptor family |
-
2002
- 2002-03-13 DE DE10212108A patent/DE10212108A1/de not_active Ceased
-
2003
- 2003-03-13 US US10/389,679 patent/US20040092718A1/en not_active Abandoned
- 2003-03-13 US US10/507,798 patent/US20060188493A1/en not_active Abandoned
- 2003-03-13 EP EP03717153A patent/EP1483293A2/de not_active Ceased
- 2003-03-13 AU AU2003221604A patent/AU2003221604A1/en not_active Abandoned
- 2003-03-13 WO PCT/DE2003/000890 patent/WO2003078468A2/de not_active Application Discontinuation
-
2006
- 2006-10-24 US US11/585,484 patent/US20070134240A1/en not_active Abandoned
-
2008
- 2008-10-14 US US12/251,039 patent/US8389016B2/en not_active Expired - Fee Related
-
2013
- 2013-03-04 US US13/783,959 patent/US20130266577A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
SUNTHARALINGAM GANESH ET AL: "Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412", NEW ENGLAND JOURNAL OF MEDICINE, THE, MASSACHUSETTS MEDICAL SOCIETY, WALTHAM, MA, US, vol. 355, no. 10, 7 September 2006 (2006-09-07), pages 1018 - 1028, XP002559375, ISSN: 0028-4793, [retrieved on 20060814], DOI: 10.1056/NEJMOA063842 * |
Also Published As
Publication number | Publication date |
---|---|
US20090246204A1 (en) | 2009-10-01 |
US20130266577A1 (en) | 2013-10-10 |
DE10212108A1 (de) | 2003-10-02 |
AU2003221604A1 (en) | 2003-09-29 |
WO2003078468A3 (de) | 2004-02-12 |
WO2003078468A2 (de) | 2003-09-25 |
AU2003221604A8 (en) | 2003-09-29 |
US8389016B2 (en) | 2013-03-05 |
US20040092718A1 (en) | 2004-05-13 |
US20070134240A1 (en) | 2007-06-14 |
US20060188493A1 (en) | 2006-08-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1483293A2 (de) | Verwendung einer an cd28 bindenden wirksubstanz zur herstellung einer pharmazeutischen zusammensetzung | |
DE69119278T2 (de) | Monoklonaler Antikörper, der mit einer neuen HLA-Determinante auf MHC-Klasse-I-Moleküle reagiert, und Verfahren zur Aktivierung von Lymphozyten | |
DE3853636T3 (de) | Antigene epitope, die sich ausschliesslich auf ige-tragenden b-lymphocyten befinden. | |
DE69422523T2 (de) | Anti-gp39 antikoerper und deren verwendungen | |
DE69031919T2 (de) | T-zell-rezeptor-peptide als heilmittel für autoimmune und bösartige krankheiten | |
DE68928915T2 (de) | Immunotherapie mit einbeziehung der cd28-stimulation | |
EP1451224B1 (de) | Peptid oder protein enthaltend ein c'-d loop der cd28 rezeptorfamilie | |
EP1519748B1 (de) | Mikropartikel mit cd28-spezifischen monoklonalen antikoerpern | |
EP1600460B1 (de) | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von B-CLL | |
DE69624824T2 (de) | Verfahren zur erkennung, identifizierung, isolierung, selektiver markierung und zielgerichteter erkennung von th1 lymphozyten mit hilfe von lag-3 protein | |
DE102004063494A1 (de) | Antikörper | |
DE19722888A1 (de) | Human-CD28 spezifische monoklonale Antikörper zur antigenunspezifischen Aktivierung von T-Lymphozyten | |
EP1600164A2 (de) | Verwendung einer an CD28 bindenden Wirksubstanz zur Herstellung einer Pharmazeutischen Zusammensetzung mit dosisabhängiger Wirkung | |
DE69735547T2 (de) | Verfahren zur induzierung von immunsupprimierten zellen und vorrichtung zu deren kultivierung | |
EP1331944B1 (de) | Verwendung cd28 spezifischer monoklonaler antikörper zur stimulation von blutzellen, welche kein cd28 tragen | |
DE69029134T2 (de) | Monoklonale antikörper zur induzierung von toleranz | |
DE69535713T2 (de) | Verfahren zur modulierung von t-zellreaktionen durch manipulation einer gemeinsamen zytokinrezeptor-gammakette | |
DE69636170T2 (de) | Monoklonaler antikörper, der spezifisch mit dem fas-liganden reagiert, und verfahren zu seiner herstellung | |
EP0499176B1 (de) | Monoklonale Antikörper gegen humane Pankreas-Inselzellen | |
WO2004056873A1 (de) | Steigerung der immunantwort durch substanzen, welche die funktion von natürlichen killerzellen beeinflussen | |
DE69028713T3 (de) | Schimäre immunoglobuline für cd4-rezeptoren | |
DE69020914T2 (de) | Monoklonale Antikörper von Ratten gegen menschliche Antigene und Verfahren zu deren Herstellung. | |
DE69928407T2 (de) | Ex vivo behandlung von allogenen und xenogenen t-zellen mit gp39-antagonisten | |
EP1025854A1 (de) | Verwendung depletorisch oder mitogen wirkender Antikörper gegen CD3/TCR in der Immuntherapie | |
DE10160516A1 (de) | Peptid oder Protein enthaltend ein C'-D Loop der CD28 Rezeptorfamilie |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20040819 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
17Q | First examination report despatched |
Effective date: 20070515 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: ARCHEM SERVICE COMPANY LIMITED |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THERAMAB GMBH |
|
19U | Interruption of proceedings before grant |
Effective date: 20061001 |
|
19W | Proceedings resumed before grant after interruption of proceedings |
Effective date: 20081110 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THERAMAB GMBH |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: THERAMAB LLC |
|
17Q | First examination report despatched |
Effective date: 20101012 |
|
APBK | Appeal reference recorded |
Free format text: ORIGINAL CODE: EPIDOSNREFNE |
|
APBN | Date of receipt of notice of appeal recorded |
Free format text: ORIGINAL CODE: EPIDOSNNOA2E |
|
APAF | Appeal reference modified |
Free format text: ORIGINAL CODE: EPIDOSCREFNE |
|
APBF | Information on invitation to file observation in appeal deleted |
Free format text: ORIGINAL CODE: EPIDOSDOBA2E |
|
APBX | Invitation to file observations in appeal sent |
Free format text: ORIGINAL CODE: EPIDOSNOBA2E |
|
APBX | Invitation to file observations in appeal sent |
Free format text: ORIGINAL CODE: EPIDOSNOBA2E |
|
APBT | Appeal procedure closed |
Free format text: ORIGINAL CODE: EPIDOSNNOA9E |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R003 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
18R | Application refused |
Effective date: 20130211 |