MXPA99011741A - Cd154 blockade therapy for therapeutic protein inhibitor syndrome - Google Patents
Cd154 blockade therapy for therapeutic protein inhibitor syndromeInfo
- Publication number
- MXPA99011741A MXPA99011741A MXPA/A/1999/011741A MX9911741A MXPA99011741A MX PA99011741 A MXPA99011741 A MX PA99011741A MX 9911741 A MX9911741 A MX 9911741A MX PA99011741 A MXPA99011741 A MX PA99011741A
- Authority
- MX
- Mexico
- Prior art keywords
- syndrome
- exogenous protein
- suffering
- manufacture
- protein
- Prior art date
Links
- 201000010874 syndrome Diseases 0.000 title claims abstract description 33
- 230000001225 therapeutic Effects 0.000 title claims abstract description 26
- 239000012268 protein inhibitor Substances 0.000 title claims abstract description 17
- 229940121649 protein inhibitors Drugs 0.000 title claims abstract description 17
- 238000002560 therapeutic procedure Methods 0.000 title description 22
- 102100003729 CD40LG Human genes 0.000 claims abstract description 83
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 44
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 44
- 108010054218 Factor VIII Proteins 0.000 claims abstract description 43
- 102000001690 Factor VIII Human genes 0.000 claims abstract description 43
- 229960000301 Factor VIII Drugs 0.000 claims abstract description 42
- 101710040446 CD40 Proteins 0.000 claims abstract description 35
- 102100013137 CD40 Human genes 0.000 claims abstract description 35
- 239000002981 blocking agent Substances 0.000 claims abstract description 19
- 230000027455 binding Effects 0.000 claims abstract description 17
- 101710003804 CD40LG Proteins 0.000 claims abstract description 14
- 239000003114 blood coagulation factor Substances 0.000 claims abstract description 9
- 230000001629 suppression Effects 0.000 claims abstract description 8
- 102000004965 antibodies Human genes 0.000 claims description 50
- 108090001123 antibodies Proteins 0.000 claims description 50
- 108010045030 monoclonal antibodies Proteins 0.000 claims description 33
- 102000005614 monoclonal antibodies Human genes 0.000 claims description 33
- 102000038129 antigens Human genes 0.000 claims description 23
- 108091007172 antigens Proteins 0.000 claims description 23
- 239000000427 antigen Substances 0.000 claims description 22
- 210000004027 cells Anatomy 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000018109 developmental process Effects 0.000 claims description 12
- 102000015081 Blood Coagulation Factors Human genes 0.000 claims description 8
- 108010039209 Blood Coagulation Factors Proteins 0.000 claims description 8
- 230000028993 immune response Effects 0.000 claims description 7
- 230000002950 deficient Effects 0.000 claims description 4
- 150000007523 nucleic acids Chemical class 0.000 claims description 4
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 210000002381 Plasma Anatomy 0.000 claims description 3
- 108010023197 Streptokinase Proteins 0.000 claims description 3
- 229960005202 Streptokinase Drugs 0.000 claims description 3
- 229940079593 drugs Drugs 0.000 claims description 3
- 239000003102 growth factor Substances 0.000 claims description 3
- 108020004707 nucleic acids Proteins 0.000 claims description 3
- 229940088598 Enzyme Drugs 0.000 claims description 2
- 102100006624 F9 Human genes 0.000 claims description 2
- 108010076282 Factor IX Proteins 0.000 claims description 2
- 102000018997 Growth Hormone Human genes 0.000 claims description 2
- 108010051696 Growth Hormone Proteins 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims description 2
- 229960004222 factor IX Drugs 0.000 claims description 2
- 239000000122 growth hormone Substances 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 230000001580 bacterial Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 32
- 239000003112 inhibitor Substances 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 8
- 230000004727 humoral immunity Effects 0.000 abstract description 7
- 230000000116 mitigating Effects 0.000 abstract description 2
- 101700048951 VSPDV Proteins 0.000 abstract 1
- 108010029697 CD40 Ligand Proteins 0.000 description 69
- 230000004044 response Effects 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 17
- 230000003044 adaptive Effects 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 229940003504 Avonex Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 210000001744 T-Lymphocytes Anatomy 0.000 description 9
- 230000003042 antagnostic Effects 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 description 8
- 230000000903 blocking Effects 0.000 description 8
- 229960000060 monoclonal antibodies Drugs 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 102200023071 HOGA1 P94S Human genes 0.000 description 7
- 102000018358 Immunoglobulins Human genes 0.000 description 7
- 108060003951 Immunoglobulins Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 108091006028 chimera Proteins 0.000 description 7
- 230000002519 immonomodulatory Effects 0.000 description 7
- 210000004369 Blood Anatomy 0.000 description 6
- 210000000265 Leukocytes Anatomy 0.000 description 6
- 241000288906 Primates Species 0.000 description 6
- 230000002068 genetic Effects 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 201000003542 factor VIII deficiency Diseases 0.000 description 5
- 230000001965 increased Effects 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000006011 modification reaction Methods 0.000 description 5
- 238000009163 protein therapy Methods 0.000 description 5
- 238000009256 replacement therapy Methods 0.000 description 5
- 210000003719 B-Lymphocytes Anatomy 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 108060008683 Tumor Necrosis Factor Receptors Proteins 0.000 description 4
- 102000003298 Tumor Necrosis Factor Receptors Human genes 0.000 description 4
- 230000001934 delay Effects 0.000 description 4
- 230000002708 enhancing Effects 0.000 description 4
- 230000028996 humoral immune response Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000001519 tissues Anatomy 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 102100000368 F8 Human genes 0.000 description 3
- 101700070229 F8 Proteins 0.000 description 3
- 230000035693 Fab Effects 0.000 description 3
- 206010018987 Haemorrhage Diseases 0.000 description 3
- 208000009292 Hemophilia A Diseases 0.000 description 3
- 210000001165 Lymph Nodes Anatomy 0.000 description 3
- 230000001419 dependent Effects 0.000 description 3
- -1 glucocefebrosidase) Proteins 0.000 description 3
- 230000002008 hemorrhagic Effects 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000001506 immunosuppresive Effects 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated Effects 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000000069 prophylaxis Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N 2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 2
- 108010055216 Anti-Idiotypic Antibodies Proteins 0.000 description 2
- 206010060945 Bacterial infection Diseases 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 229960004397 Cyclophosphamide Drugs 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 102100015239 F2 Human genes 0.000 description 2
- 101700079540 FAS Proteins 0.000 description 2
- 208000002085 Hemarthrosis Diseases 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 2
- 108010074338 Lymphokines Proteins 0.000 description 2
- 102000008072 Lymphokines Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000006551 Parasitic Disease Diseases 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 229940039716 Prothrombin Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 108091008153 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 206010053648 Vascular occlusion Diseases 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000890 antigenic Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 201000002491 encephalomyelitis Diseases 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000000051 modifying Effects 0.000 description 2
- 229960004866 mycophenolate mofetil Drugs 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- 230000002441 reversible Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 1
- PHEZJEYUWHETKO-UHFFFAOYSA-N 6-Fluoro-2-(2'-Fluoro-1,1'-Biphenyl-4-Yl)-3-Methylquinoline-4-Carboxylic Acid Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
- 101710039984 9.1 Proteins 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- 208000007502 Anemia Diseases 0.000 description 1
- 210000000612 Antigen-Presenting Cells Anatomy 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- 206010003284 Arthropathy Diseases 0.000 description 1
- 108090000206 Autoantibodies Proteins 0.000 description 1
- 102000003852 Autoantibodies Human genes 0.000 description 1
- 206010003816 Autoimmune disease Diseases 0.000 description 1
- 102000024969 Bacterial Proteins Human genes 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 108010007539 Blocking Antibodies Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229940019700 Blood coagulation factors Drugs 0.000 description 1
- 210000001185 Bone Marrow Anatomy 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229950010231 Brequinar Drugs 0.000 description 1
- 102100009787 CABIN1 Human genes 0.000 description 1
- 108010066057 CABIN1 Proteins 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000000325 Deficiency Disease Diseases 0.000 description 1
- 210000002889 Endothelial Cells Anatomy 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 210000003743 Erythrocytes Anatomy 0.000 description 1
- 102100009906 F7 Human genes 0.000 description 1
- 102100016439 FAS Human genes 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 229940094684 Feiba Drugs 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 210000001280 Germinal Center Anatomy 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- 206010018651 Graft versus host disease Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 210000004408 Hybridomas Anatomy 0.000 description 1
- 206010066130 Hyper IgM syndrome Diseases 0.000 description 1
- 208000003352 Hyper-IgM Immunodeficiency Syndrome Diseases 0.000 description 1
- 101700086956 IFNG Proteins 0.000 description 1
- 102100016020 IFNG Human genes 0.000 description 1
- 210000000987 Immune System Anatomy 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 108090001095 Immunoglobulin G Proteins 0.000 description 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000467 Interferon beta Proteins 0.000 description 1
- 102000003996 Interferon beta Human genes 0.000 description 1
- 229960001388 Interferon-beta Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000009883 Joint Disease Diseases 0.000 description 1
- 206010049550 Live birth Diseases 0.000 description 1
- 206010025135 Lupus erythematosus Diseases 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- 210000004698 Lymphocytes Anatomy 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 210000002540 Macrophages Anatomy 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108090000393 Muromonab-CD3 Proteins 0.000 description 1
- POFWRMVFWIJXHP-UHFFFAOYSA-N N-benzyl-9-(oxan-2-yl)purin-6-amine Chemical compound C=1C=CC=CC=1CNC(C=1N=C2)=NC=NC=1N2C1CCCCO1 POFWRMVFWIJXHP-UHFFFAOYSA-N 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940046781 Other immunosuppressants in ATC Drugs 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 208000008425 Protein Deficiency Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 229960001967 Tacrolimus Drugs 0.000 description 1
- 108010002487 Thomsen-Friedenreich antibodies Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 108090000373 Tissue plasminogen activator Proteins 0.000 description 1
- 102000003978 Tissue plasminogen activator Human genes 0.000 description 1
- 231100000765 Toxin Toxicity 0.000 description 1
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 230000003187 abdominal Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002424 anti-apoptotic Effects 0.000 description 1
- 230000003367 anti-collagen Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 201000008804 arthropathy Diseases 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000000740 bleeding Effects 0.000 description 1
- 231100000319 bleeding Toxicity 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229940105778 coagulation factor VIII Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 210000004748 cultured cells Anatomy 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940012413 factor VII Drugs 0.000 description 1
- 229940012426 factor X Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037240 fusion proteins Human genes 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000002443 helper T lymphocyte Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulators Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000000813 microbial Effects 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 108091008117 polyclonal antibodies Proteins 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000000306 recurrent Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 101710044770 sll1951 Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Abstract
Methods and compositions for attenuating or mitigating;suppressing;preventing;delaying onset of;or, reversing exogenous protein inhibitor syndromes, exemplified by clotting factor (e.g., Factor VIII) inhibitor syndromes. The described methods use a CD40:CD154 binding interruptor, such as CD154 blocking agent, to attenuate or ameliorate counter-adaptive, bioinhibitory humoral immunity directed against an exogenous protein of therapeutic value.
Description
CD154 BLOCKING THERAPY FOR THE THERAPEUTIC PROTEIN INHIBITOR SYNDROME
CROSS REFERENCE OF RELATED APPLICATIONS - This is a continuation in part of the previous Provisional US S.N. 60 / 050,276 filed June 20, 1997. The teachings of the Provisional patent application presented above are considered as part of the present reference.
~ FIELD OF THE INVENTION ~~ The invention relates in general to the suppression of unwanted immune responses, particularly of immune responses mediated by adaptive versus T lymphocytes. The invention relates in particular to the prevention, treatment, suppression and inversion of immunological inhibition of the therapeutic activity of exogenously administered proteins or other biological therapeutic agents.
X BACKGROUND OF THE INVENTION "zr Haemophilia A is an X-linked genetic deficiency disease that affects one of two males in every 10,000 live births, and individuals with hemophilia A have a partial or complete functional deficiency.
P946 Endogenous coagulation factor VIII (FVIII) and should receive replacement therapy of purified or recombinant FVIII. Lusher et al. (1993), 328 N. Engl. J. Med. 453-459. Approximately 15% of individuals with hemophilia A develop high titer antibody responses (eg,> 10 BU / mL) to their FVIII replacement therapy. These individuals are known as "high-response individuals." McMillan et al. (1988), 71 Blood 344-348. Said antibodies, called FVIII inhibitors, block the function (bioactivity) of the replacement FViri therapeutic agent, binding to the exogenous FVIII, administered. This immune response, humoral, versus adaptive, makes the treatment of hemorrhagic events in high-response individuals problematic. Minor hemorrhagic episodes (for example, hemarthrosis) are often successfully treated with concentrated prothrombin pools (eg, Autoplex or FEIBA, FVIII inhibitory bypass activity), but severe bleeding is difficult to control with these agents. Brettler (1996), 9 Clin. Hematol. 319-329. Most high-response individuals have low levels of FVIII inhibitory antibodies until they receive a subsequent infusion of FVIII, which stimulates (reinforces) the production of blocking antibodies. Therefore, the faith-induction of inhibitory antibodies in high-response individuals is quite predictable. Brettler (1996), 9 Clin. Hematol. 319-329. Prophylaxis with FVIII has been shown to reduce the incidence of intra-articular hemorrhage and chronic arthropathy in hemophiliacs. Liesner et al. (1996), 92 Br. Haematol. 973-978. However, due to the humoral immune response specific to FVIII in high-response individuals, they can not receive prophylactic therapy with FVIII. High-response individuals with a vigorous immune response inducible to FVIII are often treated with regular infusions of very high doses in regimens designed to induce "tolerance" to exogenous therapeutic FVIII. Brettler (1996), 9 Clin. Hematol. 319-329. In some cases, immunomodulatory agents (glucocorticoids, cyclophosphamide, intravenous immunoglobulin (IVIg)) are added to the tolerance regimens. Tolerance therapy is effective in 50% to 80% of high-response individuals. Mariani_ et al. (1994), Thromb. Haemostasis 155-158. The cost of a therapy of this type varies from $ 200,1) 00 American dollars to cas? $ l million American dollars per individual. Because infusion of FVIII_ ^ induces very high levels of inhibitors in high-response individuals, during the period of induction of tolerance - which often lasts between three and eight months, these individuals can not be treated with FVIII if they have a hemorrhage . Brettler (1996), 9 Clin. Hematol. 319-329. After a successful induction of tolerance, individuals are often maintained with prophylactic FVIII infusions two or three times a week. Brettler (1996), 9 Clin. Hematol. 319-329. The mechanism of tolerance induction employed by these protocols is not clear, but could include the induction of anti-idiotypic antibodies (Gilíes et al. (1996), 97 J. Clin. Invest. 1382-1388) or more direct suppression of B cellular clones that form the FVIII inhibitory antibodies. In addition, IVIg preparations contain anti-idiotypic antibodies to FVIII inhibitors, which could explain the efficacy of this therapy in some high-response individuals. Sultán et al. (1991), 91 Am. J. Med. 5A-35S-5A-39S. In very serious cases in which life is at risk, in which the use of FVIII therapy for hemorrhages is needed, FVIII inhibitors can be eliminated by extracorporeal immunoabsorption in anti-Ig or Protein A. Knob columns. et al. (1995), 74 Thromb. Hae ostasis 1035-1038; Gjorstrup et al. (1991), 61 Vox 7_Sang 244-250. These "protocols consume a lot of time and result in a reduction between 50% and 75% of total serum immunoglobulin (Icf) levels (Knobl et al. (1995), 74 Thromb. HaemostasTis 1035-1038), increasing
P94S is way the potential risk of infection. Similar complications of protein replacement therapy have been found in the treatment of other diseases of acquired or congenital protein deficiency, including deficiencies of other coagulation factors, plasma or blood proteins, growth factors and the like. . In addition, analogous complications have been found in other clinical conditions, such as those in which a counterpart produced recombinantly from an endogenous protein, but rare or sequestered, is administered therapeutically. For example, complications have been found
Analogous to therapies involving the administration of cytokines, lymphokines, growth factors or recombinant enzymes. An example is the administration of erythropoietin (EPO) for the treatment of anemia. Another is the "administration of interferon ß (IFN ß) for the treatment of multiple sclerosis (MS) 7 Still another is the administration of human growth hormone (hGH) for the treatment of accelerated growth." Analogous complications have also been found where a microbial protein is administered therapeutically, for example, wherein streptokinase is administered for the treatment of stroke or other type of vascular occlusion. = Therefore, there is a need for improved or more effective immunosuppressive or immunomodulatory treatments to minimize or suppress the development of inhibitory antibodies that bind to exogenously administered proteins and block the therapeutic activity of the same.In particular, there is a need for treatments that do not require pan-immunosuppression of T cells, that is, treatments that do not leave the receptor vulnerable to malignant or opportunistic infections. There is a need to 'reverse or suppress inhibitory syndromes that make it impossible to administer a necessary protein therapy, such as FVIII, to individuals who need it.
SUMMARY OF THE INVENTION "*" "It is an object of this invention to provide an immunomodulatory agent that mitigates adaptive anti-T cell responses without the need for pan-__-T-cell immunosuppression. Another object is to provide an effective immunomodulator that mitigates the severity of a humoral versus adaptive response to an exogenous protein therapy, necessary. Another object is to provide an immunomodulatory agent that delays the initiation of a humoral immune response against adaptive to an exogenous protein protein, necessary. Another object is
P94S provides an immunomodulatory agent that suppresses or reverses a humoral immune response against adaptive to an exogenous protein therapy, necessary. Another object is to provide an immunomodulatory agent that interrupts the delivery of a co-stimulatory signal to activated T cells, particularly a co-stimulatory signal for the production of immunoglobulin. A particular object is to provide a CD40: CD154 link breaker, for example, a CD154 blocking agent, to be used in therapy, in particular to be used in therapy to mitigate, delay the onset, or reverse an adaptive versus adaptive antibody response. an exogenous protein therapeutic agent, necessary, such as FVIII. The present invention is based on the discovery that the use of a CD407-CD154 linker, as a blocking agent of 'CD154, attenuates, mitigates, suppresses, prevents, delays, inhibits or reverses anti-adaptive antibody responses against antigens. Protein, without the need for pan-suppression of the immune system of the recipient. More precisely, the present invention is based on the discovery that the use of a CD154 blocking agent attenuates, alleviates, suppresses, prevents, delays, inhibits or reverses undesirable inhibitory humoral immunity that blocks bioactivity
P94S d
de = a protein therapeutically administered to an individual to replace or increase the native bioactivity of an endogenous but defective protein, such as a coagulation factor, for example, FVlfl. The invention therefore provides methods and compositions for immunomodulatory therapy for exogenous protein inhibitor syndromes. A first method attenuates or mitigates the severity ~~ of an exogenous protein inhibitor syndrome. A second method suppresses the adverse effects of the syndrome. A third method prevents the development of the syndrome. A fourth method delays the onset of the syndrome. A fifth method inhibits the development of the syndrome. A sixth method reverses the. syndrome. A seventh method retains the therapeutic efficacy of an exogenous protein, such as a therapeutic protein administered to replace or complement a native but defective protein. An eighth method restores the therapeutic efficacy of said exogenous protein. All of the above methods involve treating a subject suffering from an exogenous protein inhibitor syndrome or at risk of developing it, which refers to an adaptive humoral versus adaptive immune response that blocks (interferes with) the bioactivity of the exogenous protein, with 'a CD40 link switch: CD154, which refers to an agent that disrupts the __link of the CD40 Ligand (i.e., CD40L, also known as CD154 or the 5c8 antigen and is sometimes known in the art as gp39) with its against receiver or cognate receiver (here CD40). Preferably, the linker is a blocking agent of CD154 (CD40L), which means any agent that binds to CD154 and prevents or interferes with this link to the counter-receptors (e.g., CD40). An exemplary CD154 blocking agent is a monoclonal antibody (MAb), in particular one that has the specific antigen binding characteristics of 5c8 MAb disclosed in
United States Patent 5,474,771, whose teachings
~~ and * are considered part of this, as a reference. As mentioned above, the present invention can be practiced to attenuate or ameliorate the inhibitory syndromes directed against the exogenous proteins that are administered to replace or enhance the bioactivity of a native (endogenous) protein that is defective. it can be practiced to attenuate or improve the inhibitory syndromes directed against other exogenous proteins, including any exogenous protein that is administered for therapeutic purposes For example, the invention can be carried out to suppress, reverse or inhibiting an inhibitory response directed against any recombinantly produced therapeutic protein, in particular a therapeutic protein having a primary structure (sequence) substantially similar to (eg, virtually identical to) a native, functional, but rare protein or a protein native who is naturally kidnapped brought into a particular body structure or compartment, such as the bone marrow, a "lymph node or the central nervous system. Similarly, the invention can be practiced to suppress, reverse or inhibit an inhibitory response to a recombinant version of a native protein that is transiently expressed or expressed only in response to a specific environmental stimulus or at specific points during the development. In this manner, the invention can be practiced to attenuate or enhance an inhibitory response against a growth hormone, wound healing factor (eg, a tissue regeneration factor, stem cell factor, interferon or interleukin). , enzyme (e.g., glucocefebrosidase), blood coagulation factor (e.g., thrombin, prothrombin, Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI or Factor XII) or other plasma components (e.g., albumin, tissue plasminogen activator). In addition, the invention may be practiced to attenuate or ameliorate an inhibitory response against a foreign protein, in particular a bacterial protein (e.g., streptokinase) that is administered for therapeutic purposes (e.g., vascular occlusion treatment). Preferred subjects in whom the invention is put into practice are human subjects. In particular, the invention can be carried out in order to attenuate or improve the inhibiting syndromes of the coagulation factor in philiacs. The aforementioned objects and other objects, features and advantages of the present invention, as well as the invention itself, will be better understood from the following description of the preferred embodiments. 7"- DETAILED DESCRIPTION OF THE INVENTION * The activation of" "T cells and the immune processes dependent thereon, _ require both signals mediated by T cell receptors (TCR) and co-stimulatory signals delivered simultaneously. An important co-stimulatory signal is supplied by ligation of CD40 with an antigen presenting cell, such as a B cell, by CD40L (CD154) in a T cell. Human CD40 is a 50 kD cell surface protein expressed in cells B mature, as well as in
P946 macrophages and in activated endothelial cells. CD40 belongs to a class of receptors involved in programmed cell death, which includes Fas / CD95 and the tumor necrosis factor receptor (TNF) alpha. Human CD154 (CD40L) is a type II membrane glycoprotein of 32 kD with homology to TNF alpha that is transiently, transiently expressed, mainly in activated T cells. It has been shown that the CD40: CD154 binding is required for all T cell-dependent antibody responses. In particular, the CD40: CD154 linkage provides anti-apoptotic and / or lymphokine stimulatory signals. The importance of the CD40: CD154 link in promoting T cell-dependent biological responses was more fully appreciated when it was discovered that the hyper-IgM syndrome linked to X (X-HIGM) in humans is the phenotype resulting from the genetic absence of Functional CD154. Affected individuals have normal or high IgM levels, but fail to produce IgG, IgA or IgE antibodies and suffer from recurrent bacterial and parasitic infections, sometimes severe, as well as an increased incidence of lymphomas and abdominal cancers. A similar phenotype is observed in animals that give nullizygotes for the gene coding for CD154 (knockout animals). B cells of CD154 nullizygotes can produce IgM in the absence of CD40: CD154 binding, but do not have the capacity
P94S to undergo isotype switching or to survive normally after affinity maturation. Histologically, the germinal centers of the lymph nodes fail to develop properly and the
^ - ___ B memory cells are present or underdeveloped. Functionally, these defects contribute to a severe reduction or absence of a secondary (mature) antibody response. Defects in cellular immunity are also observed, manifested by an increased incidence of bacterial and parasitic infections. Many of these cell-mediated defects are reversible by administration of IL-12 or IFN-gamma. These observations justify the approach that the CD4Ó: CD154 normal linkage promotes the development of immune responses of Type I T helper cells. Blockade of the CD404: CD154 interaction during immunization with protein antigens can specifically block the response of antibody to that antigen in mice Foy et al (1993), 178 J. Exp. Med. 1567-1575.For example, anti-CD154 antibodies can block the induction of anti-collagen antibodies in collagen-induced arthritis. et al. (1993), 261 Science 1328-1330. Anti-CD154 antibodies can reduce anti-dsDNA and anti-nucleosomal autoantibodies in mice with spontaneous lupus. '"Mohán et al. (1995), 154 J.
P946 Immúñol. 1470-1480. In addition, "anti-CD154 antibodies can reduce symptoms in" mice with experimental ato-immune encephalomyelitis (EAE), a model of MS. Similar results have been reported in models of graft-versus-host disease in rodents, glomerulonephritis induced by mercury chloride, and inflammatory bowel disease. In this way, the blocking of CD40: CD154 can provide potentially potent therapies for attenuating or ameliorating unwanted humoral immune responses, particularly in the context of autoimmune diseases or indeed, when the target antigen is a protein of therapeutic value, a value that is prevented by an immune response against adaptive. However, despite numerous reports of promising results, studies conducted in models of immunological versus adaptive disease (for example, autoimmunity) in Troedores, have been scarcely related to the results of tests in real disease contexts or even in model systems. preclinical studies of larger animals (eg, primates). - Protocols to evaluate are presented here. the effects of a preferred CD154 blocking agent, a Jjumanized MAb having the antigen binding properties specific to MAb 5C8 (Léderman et al., J. Exp. Med.
P946 175: 1091-1101, 1992), in preclinical models considered as prognostic of therapeutic efficacy in the treatment of - exogenous protein inhibitor syndromes. Specifically, the models herein involve CD154 blocking therapy to attenuate or enhance specific bioinhibitory humoral immunity for coagulation factors (e.g., FVlfl) and lymphokines (e.g., IFN ß). These models can be adapted, by no more than routine manipulation, to be used in establishing the efficacy of CD154 blocking therapy to attenuate or enhance inhibitory humoral immunity against any protein of therapeutic value. The following discussion illustrates and exemplifies the diversity of contexts and circumstances in which the invention can be brought into "practice," as well as providing proof-of-principle studies involving specific embodiments of the invention.
SUBJECTS FOR TREATMENT The invention can be used for the treatment or prophylaxis of any mammalian subject "that" needs protein replacement therapy or has already received it, indeed any protein therapy. Subjects who "" consequently suffer from exogenous protein inhibitor syndrome or are at risk of developing it.
For example, hemophiliacs who are treated with exogenous FVIIT are at considerable risk of becoming "high-response individuals", where after FVIII loses efficacy for the intended purpose of suppressing hemorrhagic events. Accordingly, the invention is particularly suitable for use with hemelotics. The procedures for determining whether a haemophiliac has developed an inhibitory response against FVIII administered therapeutically and / or if it has become an individual ie high response are well known. See, for example, Hematology: Clinical and Laboratory Practice, vol. 2, Bick, ed. , Mosby-Year Book, Inc., publ. (1993), p. 1544-1548. Preferably, the mammalian subject is a primate, more preferably a superior primate, preferably a human superlative. In other embodiments, the subject may be another mammal that suffers from an exogenous protein inhibitor syndrome or is in need of developing it, particularly a mammal of commercial importance, a companion animal or other valuable animal such as a member of the species in danger of extinction. In this way, the subjects also include, in a non-exclusive manner, sheep, horses, cattle, goats, pigs, dogs, rabbits, guinea pigs, hamsters, gerbils, rats and mice. ~~
P946 CD40: CD154 Linkers and Emplificatives * __ Therapeutic compounds useful in carrying out the present invention include any compound that blocks the interaction of cell surface CD40 (e.g., in B cells) with CD40L ( CD154) expressed, for example, on the surface of activated T cells The CD40 binding compounds: CD154, such as the blocking agents of CD154, which are specifically considered include polyclonal antibodies and monoclonal antibodies (MAbs), as well as derivatives of antibodies such as chimeric molecules, humanized molecules, molecules with reduced effector functions, bispecific molecules and antibody conjugates In a preferred embodiment, the antibody has practically the same specific antigen binding characteristics as MAb 5c8, as described in the US Pat. United States 5,474,771, which is considered part of this , as a reference In a generally quite preferred embodiment, the antibody is a humanized 5c8 (hu5c8). Other known antibodies against CD154 include antibodies ImxM90, ImxM91 and ImxM92 (disclosed by Immunex Corp., Seattle WA), an anti-CD40L MAb commercially available from Acell (clone 24-31), catalog # 353-020, Bayport, MN ) and an anti-CD154 MAb commercially available from Genzyme (Cambridge, MA,
P946 catalog # 80-3703-01). An anti-CD154 MAb from PharMingen (San Diego, catalog # 33580D) is also commercially available. Numerous additional anti-CD154 antibodies have been produced and characterized (see, for example, WO 96/23071 of ~ T3ristol-Myers Squibb, the specification of which is hereby incorporated by reference). The invention also includes the use of CD154 blocking agents which are derived or genetically engineered from the aforementioned and equivalent _MAbs, as complete Fab fragments, F (ab ') 2 compounds / VH regions, Fv regions, single chain (see, for example, WO 96/273071), polypeptides, structures constructed from fusion of polypeptides, fusions of CD40 (such as CD40Ig, according to Hollenbaugh et al., J. Immunol., Meth. 188: 1-7, 1995, which is considered part form of the present, as a reference) and small molecule compounds such as small semi-peptidic compounds or non-peptidic compounds, all with the ability to block or interrupt the CD40: CD154 linkage. The procedures for designing, screening and refining small molecules are provided in PCT / US96 / 10664, filed June 21, 1996, the specification of which is hereby incorporated by reference.
P94S _- In this way, the invention can be carried out with CD154 blocking agents, t-MAb derivatives, generated using standard recombinant DNA techniques (Winter and Milstein, Nature 349: 293-299, '1991). A class of said CD154 blocking agents includes chimeric antibodies or fusion proteins constructed by joining nucleic acid which codes for the antigen binding domain of a non-human mammalian antibody (eg, mouse or rat antibody) of specificity. desired to a nucleic acid encoding a human immunoglobulin (Ig) constant region. Cabilly et al., U.S. Patent No. 4, 6, 6, 5, 667; Morrison et al., Proc. Nati Acad. Sci. 81: 6851-55, 1984. The polypeptides of chimeric antibodies expressed from these constructed structures generally have less immunogenicity, when they are used for human therapy or prophylaxis than the non-human antibody from which they are derived. derived the chimera. A second class of such CD154 blocking agents includes recombinant "humanized" or "primatized" antibodies. The humanized or primatized antibodies are antibodies that have been "genetically obtained from antibodies of non-human mammals having the desired specificity, substituting some or all of the codons for amino acids not required in the" antigenic "linkage.
P946 codons for amino acids of the corresponding regions of a light or heavy human Ig or primate chain gene. That is, they are chimeras comprising mainly human immunoglobulin sequences in which the regions responsible for the specific antigen binding have been genetically introduced "(see, for example, PCT patent application WO 94/04679). Generally, in vivo immunogenicity is even lower than chimeric antibodies.To currently practice the invention, a humanized MAb having virtually the same antigenic specificity as MAb 5c8 (here, hu5c8) is preferred. X Other class of agents MAb-derived CD154 blockers useful in the invention include human antibodies, which can be produced in transgenic non-human mammals, in which one or more immunoglobulin transgenes have been integrated.They can be used as a source of -splenocytes to produce human hybridomas , as described in U.S. Patent 5,569,825, Of course, any The specific antigen binding fragment of one of the aforementioned MAbs or MAb-derived therapeutic agent can be used in the present invention, provided the fragment
P946 is "large enough to sterically prevent the binding of CD154 to its counter-receptor." Thus, the MAb fragments and the univalent MAbs can be used.The univalent antibodies comprise a heavy chain / light chain dimer attached to the Fc region (or stem) of a second heavy chain The "Fab region" refers to those portions of the chains that are more or less equivalent or analogous to the sequences comprising the Y-branched portions of the heavy chain and the light chain in its entirety and that collectively
(in 'aggregates') have been shown to exhibit antibody activity. A Fab protein includes aggregates of a heavy chain and a light chain (commonly known as Fab!), As well as tetramers that correspond to the two branched segments of the Y antibody, (commonly known as F (ab) 2), either of the foregoing is added covalently or non-covalently, provided that the aggregation has the ability to react selectively with a particular antigen or a family of antigens. In addition, standard recombinant DNA techniques can be employed to modify the binding affinities of recombinant antibodies with their antigens by modifying amino acid residues in the vicinity of the antigen binding sites. The binding affinity to the antigen of a humanized antibody can be increased by mutagenesis based on molecular modeling (Quéen et al., Proc.Nat.Acid.Sci.86: 10029-33, 1989. PCT patent application WO 94/04679 ). It would be desirable to increase or decrease the affinity of the antibodies for CD154 depending on the type of tissue selected as target or on the particular treatment scheme conceived. This could be done using phage display technology (see, for example, Winter et al., Ann. Rev. Immunol. "12: 433-455, 1994; and Schier et al., J. Mol. Biol. 255: 28- 43, 1996, which is considered part of the present, for reference.) For example, it would be advantageous to treat a patient with constant levels of antibodies with reduced CD154 affinity for semi-prophylactic treatments. The increased CD154 could be advantageous for short-term treatments.
Administration Routes _ The switches of the CD40: CD154 linkage, among the "~ which include CD154 blocking agents, used in the invention can be administered in any way that is medically acceptable." Depending on the specific circumstances, Local or systemic administration may be convenient.
P946 Preferably, the agent is administered via a parenteral route eg, intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intraventricular, intraperitoneal, subcapsular, intracranial, intraspinal, infusion or inhalation injection. The agent can also be administered by implantation of an infusion pump or a biodegradable or biocompatible sustained release implant into the recipient host, either before or after tissue implantation of the donor. Alternatively, certain compounds of the invention or formulations thereof may be suitable for oral or enteral administration. Still other compounds of the invention will be suitable for topical application. In other modalities, the link switch
CD40: CD154 is supplied indirectly to the receptor, by administering a vector or other expressible genetic material that codes for the switch. The genetic material is internalized and expressed in cells or tissue of the receptor, whereby the switch is produced in situ. For example, a suitable constructed nucleic acid structure would comprise a sequence encoding one or more of the immunoglobulin (Ig) MAb 5c chains as set forth in U.S. Patent 5,474,771. Other structures
Suitable P946 constructs would comprise sequences encoding chimeric or humanized versions of the MAb 5c8 Ig chains or antigen binding fragments thereof. Still other suitable constructed structures would comprise sequences that code for part of other specific or all CD154 MAbs. The structure is supplied systemically or locally, for example, to a location adjacent to the tissue implantation site that expresses insulin. Alternatively, the vector or other genetic material encoding the switch is internalized in a suitable population of isolated cells to "produce switch-producing host cells." Then these host cells are implanted or infused into the receptor, either locally or systemically to provide In situ production of the CD40 linker switch: CD154 Suitable host cells include cultured cells, such as immortalized cells, as well as cells derived from the recipient (eg peripheral blood or lymph node cells, such as natural killer cells (NK) "J •
Formulation In general, the compound (s) used in the
P946 of the invention are suspended, dissolved or dispersed in a pharmaceutically acceptable excipient or carrier. The resulting therapeutic composition does not adversely affect receptor homeostasis, particularly the electrolyte balance, so that an exemplary vehicle comprises normal physiological saline (NaCl 0.15M, pH 7.0 to 7.4) Another exemplary vehicle comprises sodium phosphate. 50 mM sodium, 100 mM sodium chloride Many other acceptable carriers are well known in the art and are described, for example, in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., 1990. Acceptable vehicles may include biocompatible salts , inert or bioabsorbable, buffering agents, oligo- or polysaccharides, polymers, viscosity-enhancing agents, preservatives and the like. ~ Any CD40: CD154 link breaker, such as a CD154 blocking agent, which is used to carry out the invention is formulated to deliver a pharmaceutically effective or therapeutically effective amount or dose, which is an amount sufficient to produce a detectable, preferably medically beneficial, effect in the recipient. Medically beneficial effects would include preventing, delaying or mitigating - the deterioration of the medical condition of the
P946 receptor or improve it in a "perceptible" manner As an example, the titre of a specific inhibitory antibody to a necessary exogenous protein therapeutics can be suppressed or diminished.Thus, for example, an effective amount of a therapeutic compound of the invention, as a CD154 blocking agent, is any amount that perceptibly restores the therapeutic efficacy of protein therapeutics An optimal effective amount is that which substantially releases the subject from antibodies against adaptives that cause the inhibitor syndrome.
Dose and Frequency of Treatment The amount and frequency of the dosage for any particular compound to be used in the practice of the invention is within the reach of the experience and clinical judgment of the persons practicing the medical technique, for example, physicians. . The general dosage and administration regimen is established by clinical and preclinical tests, which involve studies but routinely to determine effective parameters of administration, for example, the optimum ones for the desired compound. Even after "such recommendations are made, the doctor will often vary those doses for the different subjects based on a
P94S diversity of considerations, such as age, medical status, weight, sex of the subject and concurrent treatments with other drugs. Determining the effective dose and administration rate for each CD40: CD154 linker switch used in the invention is a routine matter for those skilled in the medical and pharmaceutical arts. The amount of the dose and the time of treatment should be sufficient to "produce a clinically beneficial change in one or more indices of the health status of the subject." - Treatment times and exemplary dosage regimens are established in the early test studies. To exemplify considerations of dosage for an anti-CD154 compound, the following examples of administration strategies for an anti-CD154 MAb are given: The amounts of the doses could easily be adjusted for other types of CD154-blocking compounds. In general, simple doses of approximately between 0.05 and 50 mg / kg of body weight of the subject are considered, with more frequent doses in the range between 1 and 20 mg / kg To begin the CD154 blocking therapy prophylactically, when the subject is in remission or for emergency therapy of acute illness, an effective dose of MAb varies between approximately 1 mg / kg d body weight and approximately 20 mg / kg of body weight, administered
P946 daily or at intervals ranging from two to five days, for a period of approximately three weeks. The therapy can then be maintained by administering the MAb intermittently, in doses ranging from about 0.1 mg / kg of body weight to about 20 mg / kg of body weight. For maintenance purposes, the interval between doses may vary between approximately one week and up to approximately three months. In the present, a one month (four week) interval between doses is preferred. The blocking therapy of CD154 can be carried out, if desired, serially or in combination with conventional immunosuppression therapy. A conventional immunosuppressive agent (eg, a corticosteroid or a calcineurin inhibitor) can be co-administered at any time during CD154 blockade therapy if the physician considers it prudent. Alternatively, a CD154 blocking MAb may be conjugated with a conventional agent. This advantageously allows administration of the conventional agent in an amount less than the conventional dose, for example, less than about 50% of the conventional dose, when the agent is administered as monotherapy. Consequently, the presence of many side effects associated with that agent should be avoided. So,
P946 according to this invention, CD154 blocking MAbs can be used together with other agents directed to B cells, such as anti-CD19, anti-CD28 or anti-CD20 antibody (unconjugated or radiolabeled), IL-14 antagonists, LJP394 (blocker LaJolla Pharmaceuticals receptor), IR-1116 (small molecule Takeda) and monoclonal anti-idiotype Ig antibodies. Alternatively, combinations may include agents directed to T cells / B cells, such as
* _. CTLA4Ig, IL-2 antagonists, IL-4 antagonists, IL-6 antagonists, receptor antagonists, anti-CD80 / CD86 monoclonal antibodies, TNF, LFA1 / ICAM antagonists, VLA4 / VCAM antagonists, brequinar conjugates and IL-2 toxin (eg, DAB), prednisone, anti-CD3 MAb (OKT3), mycophenolate mofetil (MMF), cyclophosphamide and other immunosuppressants as blockers of * calcineurin signal, including but not limited to, tacrolimus ( FK506). The combinations may also include agents directed to T cells as CD4 antagonists, CD2 antagonists and IL-12. 7 Pre-Clinical Model Systems ^ to Evaluate CD40 Switch Treatment Regimens: CD154 Examples of exemplary, currently preferred, systems are listed below to test the efficacy of a CD40 switch compound: CD154 (eg, an anti-CD40L compound or a blocking agent of CD154, as a MAb having the specificity of MAb 5c8). In each system, routine modifications or adaptations may be made to adapt the published techniques as necessary to evaluate the effects of any CD40: CD154 switch compound on the status of protein-inhibitor titers in the animal model. Some exemplary modifications are mentioned in the following brief summaries; however, many other suitable modifications will be apparent to the skilled practitioner and are considered herein.
a Mouse Model Knocked Out for Haemophilia A. Recently, researchers at the American Red Cross established a colony of mouse offspring that gave nulligothic ("knockout") mice for native murine FVTTI. Bi et al. (1995), 10 Nature Genetics 119. These mice exhibited all the relevant pathologies of human hemophilia A. In addition, the mouse model accurately mimics the etiology of these pathologies of the disease: hereditary or congenital absence of native, biologically active FVIII It has been reported that the administration of FVIII boluses, administered in the manner that corresponds to conventional FVIII replacement therapy, triggers the "production of antibodies
P94S FVIII inhibitors in these "mice" Quian et al. (1996), 88 -Blood 656a (suppl.). Other routes of administration, specifically constitutive replacement via the integration of an adenoviral vector encoding functional FVIII, seem to present in general protein therapy in a less immunogenic context. Coñnely et al. (1998), 91 Blood 3273-3281. The effects of a CD154 blocking agent, eg, a murine anti-CD154 in the development of "high response individuals" in a population of the hemophiliac mice described above, can be evaluated in general terms as follows: the antigen ( FVIII) can be injected as a bolus dose (eg, 0.2 ug) on study days 0 and 14. On or around day 54 of the study, a blood sample can be taken and analyzed (using ELISA techniques). routine) to check for the presence of FVIII inhibitory antibodies. Then, a test group (5 or more animals) can be provided; a similar number of animals can be assigned to one or more appropriate control groups) with a suitable dose of murine anti-CD154 (eg, 250 ug, intraperitoneal or intravenous), for example, on study days 55 and / or 57 or around them. A dose of FVIII stimulation may be administered on or around study day 56. After, you can take
P946 blood samples and analyzed on the appropriate study days to monitor the development of the test group, the suppression or reversal of a secondary antibody response to FVIII inhibitors, for example, blood can be obtained in the days of study 74, 81 and 96 or around them, taking into account some individual variations among animals in this test group, it is expected that CD154 blockade therapy will blunt or suppress secondary humoral immunity of FVIII.
Chimeric Mouse Model SCID-hu -7 This chimeric mouse model system, originally reported by Mosier et al. (1988), 335 Nature 256-259, is based on immunological rescue (functional reconstitution) of mice with severe combined immunodeficiency (SCID) by grafting normal human peripheral blood leukocytes (PBLs), resulting in a human mouse chimera stable. This system has been used in numerous investigations of the behavior and dynamic interactions of human lymphocytes in vivo. Significantly, this model system has been used to "investigate the effects of CD404: CD154 switching agents on the response of normal human leukocytes to murine erythrocytes (used as a model antigen).
P946 Chen et al. (1995), 155 J. Immunol. 2833-2840. In this study, MAbs ant? -CD40 and anti-CD154 showed that they modulate downward the production of total human Ig. This model system allows to evaluate the effects of a human ant? -CD154, for example, hu5C8, on human T cells in vivo, using any desired protein as a test antigen. In a proper modification, mouse chimeras can be created. SCID-hu by grafting human PBLs from hemophiliacs as high-response individuals. Of course, this proposal can be taken with PBLs from any human affected by an exogenous protein inhibitor syndrome. In the case of SCID-hu mice made from an individual with a high hemophilic response, appropriate numbers of mice can be assigned to study groups (eg, from 2 to 5 or more as follows: Group A (hu5C8 and FVIII), Group B (hu5C8 only), Group C (FVIII only), Group D (vehicle only), group E (control Ig and FVIII), Group F (Ig "control only), the indicated test article and / or control is mixed with the hu PBLs at the time of grafting and is administered intraperitoneally on study days 2 and / or _4 or around them.The kinetics of the resulting FVIII inhibitory response can be momtorear by standard techniques (ELISA) using blood taken at appropriate intervals during a
P946 period of several weeks. It is expected that treatment with hu5C8 will blunt or abrogate humoral immunity secondary to FVIII.
Models of Non-Human Primates Model AVONEX (IFN). Rhesus monkeys or cynomologus are assigned to appropriate study groups, for example, two or four animals per group, as follows: Group 1 (control antigen (HAS), 50 ug / kg and hu5C8, 5, mg / kg), Group 2 (vehicle and hu5C8; 5 mg / kg), Group 3
(AVONEX, 50 ug / kg and hu5C8, 5 ^ mg / kg), Group 4 (AVONEX, 50 ug / kg and hu5C8, 5 mg / kg), Group 5 (vehicle and hu5C8, 5 mg / kg). Groups 1, 2 and 3 receive hu5C8 starting on study day 1 and approximately every second or third day after. Groups 4 and 5 receive hu5C8 starting on study day 17 and approximately every second or third day after. All AVONEX groups receive AVONEX every "third day starting on or around study day 3. The development and kinetics of AVONEX inhibitory antibodies are monitored using routine ELISA techniques, and clear differences are expected between AVONEX groups treated with AVONEX. hu5C8 or untreated Specifically, pretreatment with hu5C8 is expected to blunt or substantially abrogate the development of AVONEX inhibitory antibodies.
P946 with hu5C8 is expected to substantially suppress or reverse the development of humoral immunity secondary to AVONEX.
The model described above can be routinely adapted to evaluate the effects of hu5C8 or another CD154 blocking agent on primary and / or secondary inhibitory responses to other model antigens, including exogenous protein therapeutics. For example, appropriate routine, protocol and dose level modifications can be made to evaluate the behavior of FVIII or other coagulation factor in primates that are provided with prophylactic or therapeutic regimens of CD154 blockade therapy.
Equivalents The invention may be expressed in other specific forms without deviating from the spirit or essential characteristics thereof. Therefore, the aforementioned modalities are considered in all illustrative aspects of the invention set forth herein, rather than limiting. Thus, the scope of the invention is indicated by the appended claims rather than by the foregoing description and it is intended that all changes that arise within the meaning and field of equivalence of the claims are "embraced therein.
P946
Claims (12)
- CLAIMS: 1. Use of a CD40: CD154 link breaker in the manufacture of a medicament to attenuate the severity of the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of suffering from it.
- 2. Use of a CD40: CD154 link switch in the manufacture of a medicament for suppressing the adverse effects of the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of suffering from it.
- 3. Use of a CD40: CD154 link breaker in the manufacture of a medicament to prevent the development of the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of suffering from it. _
- 4. Use of a CD40: CD154 link breaker in the manufacture of a medicament for delaying the onset of the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of suffering from it.
- 5. Use of a CD40: CD154 link switch in the manufacture of a drug to inhibit the development of the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of P946 suffer it.
- 6. Use of an eXXace CD40: CD154 switch in the manufacture of a drug to reverse __ the exogenous protein inhibitor syndrome in a subject suffering from the syndrome or at risk of suffering from it. J-
- 7. Use of a CD40: CD154 link breaker in the manufacture of a medicament for preserving the therapeutic activity of an exogenous protein in a subject that is treated with the exogenous protein. -
- 8. Use of a CD40: CD154 link switch in J.a manufacture of a medicament for restoring the therapeutic activity of an exogenous protein in a subject that is treated with the exogenous protein to which the subject has developed an immune response.
- 9. Use according to claims 1, 2, 3, 4, 5, 6, 7 or 8, wherein the linker CD40: CD154 is: a) a blocking agent of CD154 (CD40L); or b) a monoclonal antibody; or ~ "c) a monoclonal antibody that also has the antigen binding characteristics" specific for the 5C8 antibody produced by ATCC Accession No. HB 10916.
- 10. Use according to claims 1, 2, 3, 4, 5, 6 , 7 or 8, where the exogenous protein is: "a) a substitute for an endogenous protein, but defective, or b) a protein that has practically the same primary structure as a corresponding endogenous protein, or c) produced from a cell isolated host harboring an expressible recombinant nucleic acid encoding the exogenous protein, od) of bacterial origin, or e) a coagulation factor, which includes Factor VIII or Factor IX; of) a growth hormone, a factor of wound healing, growth factor, cytokine, lmfocin, enzyme, coagulation factor or plasma component, or zzz g) streptokinase
- 11. Use according to claims 1, 2, 3, 4, 5, 6, 7 or 8, where the subject is human
- 12. Use according to claim 11, wherein the human is hemophilic. P946
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/050,276 | 1997-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99011741A true MXPA99011741A (en) | 2000-06-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1425028B1 (en) | Use of il-18 inhibitors for the treatement or prevention of sepsis | |
US8440189B2 (en) | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders | |
EP1034001B1 (en) | Cd154 blockade therapy for therapeutic protein inhibitor syndrome | |
KR100575069B1 (en) | Use of a cd40:cd154 binding interruptor to prevent counter-adaptive immune responses, particularly graft rejection | |
CZ300364B6 (en) | Pharmaceutical preparation containing BCMA polypeptide or antibody against this polypeptide | |
JPH08505365A (en) | Treatment of autoimmune and inflammatory diseases | |
KR101800467B1 (en) | Methods and compositions for treating lupus | |
KR100584704B1 (en) | Soluble lymphotoxin-beta receptors, anti-lymphotoxin receptor antibodies, and anti-lymphotoxin ligand antibodies as therapeutic agents for the treatment of immunological diseases | |
EP0966302B1 (en) | Methods of therapeutic administration of anti-cd40l compounds | |
KR100622960B1 (en) | Treatment of follicular lymphomas using inhibitors of the lymphotoxinlt pathway | |
PL195264B1 (en) | Reversal of viral-induced systemic shock and respiratory distress by blockade of the lymphotoxin beta pathway | |
WO1998039026A2 (en) | Methods of therapeutic administration of anti-cd40l compounds | |
WO1999000143A1 (en) | Cd154 blockade therapy for autoimmune diseases | |
MXPA99011741A (en) | Cd154 blockade therapy for therapeutic protein inhibitor syndrome | |
Nesbitt et al. | Certolizumab pegol: a PEGylated anti-tumour necrosis factor alpha biological agent | |
PL190316B1 (en) | Cd154 blocking therapy for treating a therapeutic protein inhibitor syndrome | |
MXPA99010571A (en) | Use of a cd40:cd154 binding interruptor to prevent counter adaptive immune responses, particularly graft rejection |