WO1996032137B1 - Methods of inducing immune tolerance using immunotoxins - Google Patents
Methods of inducing immune tolerance using immunotoxinsInfo
- Publication number
- WO1996032137B1 WO1996032137B1 PCT/US1996/005087 US9605087W WO9632137B1 WO 1996032137 B1 WO1996032137 B1 WO 1996032137B1 US 9605087 W US9605087 W US 9605087W WO 9632137 B1 WO9632137 B1 WO 9632137B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- immunotoxin
- donor
- recipient
- cell
- crm9
- Prior art date
Links
- 231100000608 Immunotoxin Toxicity 0.000 title claims abstract 33
- 108010004484 Immunotoxins Proteins 0.000 title claims abstract 33
- 230000002637 immunotoxin Effects 0.000 title claims abstract 33
- 239000002596 immunotoxin Substances 0.000 title claims abstract 33
- 230000001939 inductive effect Effects 0.000 title claims abstract 3
- 210000004027 cells Anatomy 0.000 claims abstract 15
- 102000016607 Diphtheria Toxin Human genes 0.000 claims abstract 8
- 108010053187 Diphtheria Toxin Proteins 0.000 claims abstract 8
- 210000000056 organs Anatomy 0.000 claims abstract 8
- 108090001123 antibodies Proteins 0.000 claims abstract 7
- 102000004965 antibodies Human genes 0.000 claims abstract 7
- 210000001744 T-Lymphocytes Anatomy 0.000 claims abstract 4
- 230000035772 mutation Effects 0.000 claims abstract 4
- 230000037361 pathway Effects 0.000 claims abstract 4
- 206010013023 Diphtheria Diseases 0.000 claims abstract 3
- 231100000654 Protein toxin Toxicity 0.000 claims abstract 3
- 102000004169 proteins and genes Human genes 0.000 claims abstract 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract 3
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- 210000001519 tissues Anatomy 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims 6
- 230000001861 immunosuppresant Effects 0.000 claims 5
- 239000003018 immunosuppressive agent Substances 0.000 claims 5
- 230000002992 thymic Effects 0.000 claims 4
- 206010059512 Apoptosis Diseases 0.000 claims 3
- 230000006907 apoptotic process Effects 0.000 claims 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims 2
- 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 claims 2
- 108010036949 Cyclosporine Proteins 0.000 claims 2
- 229960001265 ciclosporin Drugs 0.000 claims 2
- 102000027675 major histocompatibility complex family Human genes 0.000 claims 2
- 229960004866 mycophenolate mofetil Drugs 0.000 claims 2
- 230000003000 nontoxic Effects 0.000 claims 2
- 231100000252 nontoxic Toxicity 0.000 claims 2
- 210000001185 Bone Marrow Anatomy 0.000 claims 1
- 108010071134 CRM197 (non-toxic variant of diphtheria toxin) Proteins 0.000 claims 1
- 210000002216 Heart Anatomy 0.000 claims 1
- 210000000936 Intestines Anatomy 0.000 claims 1
- 210000004153 Islets of Langerhans Anatomy 0.000 claims 1
- 210000003734 Kidney Anatomy 0.000 claims 1
- 210000004185 Liver Anatomy 0.000 claims 1
- 210000004072 Lung Anatomy 0.000 claims 1
- 210000004698 Lymphocytes Anatomy 0.000 claims 1
- 210000000496 Pancreas Anatomy 0.000 claims 1
- 210000001541 Thymus Gland Anatomy 0.000 claims 1
- 230000000735 allogeneic Effects 0.000 claims 1
- 239000000427 antigen Substances 0.000 claims 1
- 102000038129 antigens Human genes 0.000 claims 1
- 108091007172 antigens Proteins 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 206010018651 Graft versus host disease Diseases 0.000 abstract 1
- 208000009329 Graft vs Host Disease Diseases 0.000 abstract 1
- 206010021425 Immune system disease Diseases 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 239000011886 peripheral blood Substances 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 abstract 1
Abstract
Provided is a method of treating an immune system disorder not involving T-cell proliferation, comprising administering to the animal an immunotoxin comprising a mutant diphtheria toxin moiety linked to an antibody moiety which routes by the anti-CD3 pathway, or derivatives thereof under conditions such that the disorder is treated. Thus, the present method can treat graft-versus-host disease. Also provided is a method of inhibiting a rejection response by inducing immune tolerance in a recipient to a foreign mammalian donor tissue or cells, comprising the steps of: a) exposing the recipient to an immunotoxin so as to reduce the recipients' peripheral blood T-cell lymphocyte population by at least 80 %, wherein the immunotoxin is anti-CD3 antibody linked to a diphtheria protein toxin, wherein the protein has a binding site mutation; and b) transplanting the donor cells into the recipient, whereby a rejection response by the recipient to the donor organ cell is inhibited, and the host is tolerized to the donor cell.
Claims
AMENDED CLAIMS
[received by the International Bureau on 22 January 1997 (22.01.97);
new claims 28-38 added; remaining claims unchanged (5 pages)]
1. A method of inhibiting a rejection response by inducing immune tolerance in a recipient to foreign mammalian donor cells, comprising the steps of:
a ) exposing the recipient to an immunotoxin so as to safely reduce the recipients's T-cell
lymphocyte population by at least 80%, wherein the immunotoxin is antl-CD3 antibody linked to a
diphtheria protein toxin, wherein the protein has a binding site mutation that reduces binding; and
b) transplanting the donor cells into the recipient, such that a rejection response by the recipient to the donor organ cell is inhibited.
2. The method of claim , wherein the donor cells constitute an organ.
3. The method of claim 1 , wherein the donor cells constitute tissue from an organ.
4. The method of claim 1, wherein the donor cells are allogeneic.
5. The method of claim 1, wherein the donor cells are xenogeneic.
6. The method of claim 1, wherein the exposure step reduces the recipient's T-lymphocyte population by at least 95%.
7. The method of claim 1, wherein the immunotoxin is anti-CD3-CRM9.
8. The method of claim 1, further comprising
administering to the thymus gland a thymic apoptosis signal.
5. The method of claim 1, wherein the thymic apoptosis signal comprises a ccrticosteroid.
10. The method of claim 1, further comprising thymic injection of lymphocytes having MHC antigen of the same haplotype as the MHC of the donor cell.
11. The method of claim 1, further comprising administering an immunosuppressant compound.
12. The method of claim 11, wherein the
immunosuppressant compound is cyclosporin,
13. The method of claim 11, wherein the
immunosuppressant compound is mycophenolate mofetil.
14. The method of claim 8, further comprising administering an immunoβuppresaant compound.
15. The method of claim 14, wherein the
immunosuppressant compound is cyclosporin.
16. The method of claim 14, wherein the
immunosuppressant compound is mycophenolate mofetil.
17. The method of claim 1, wherein the donor organ cell is from a live donor, and wherein the
immunotoxin is administered from 15 hours to 7 days before the transplanting step.
18. The method of claim 1, wherein the donor organ cell is from a cadaver and is from kidney, and
wherein the immunotoxin is administered from 6 to 15 hours before the transplanting step.
19. The method of claim 1, wherein the donor organ cell is from a cadaver and is selected from the group consisting of heart, lung, liver, pancreas,
pancreatic islets and intestine, and wherein the immunotoxin is administered from 0 to 6 hours before the transplanting step.
20. The method of claim 1, further comprising administering donor bone marrow at the same time, or after, the exposure step.
21. The method of claim 8, wherein the thymic apoptosis signal comprises lymphoid irradiation.
22. The method of claim 1, wherein the immunotoxin comprises a mutant diphtheria toxin moiety linked to a single chain variable region antibody which routes by the anti-CD3 pathway, or derivatives thereof.
23. The method of claim 1, wherein the immunotoxin is scUCHTl-DT390.
24. The method of claim 1, further comprising administering a non-toxic mutant of diphtheria toxin before, or at the same time as the exposure step.
25. The method of claim 24, wherein the non-toxic mutant of diphtheria toxin is CRM197.
26. The method of claim 1, wherein the immunotoxin is an anti-Vβ-CRM9.
27. The method of claim 4, wherein the immunotoxin is an anti-V"-CRM9.
28. An immunotoxin for use in the manufacture of a medicament for the treatment of organ rejection in a transplant recipient.
29. The immunotoxin of claim 28, wherein the immunotoxin comprises an anti-CD3 antibody linked to a diphtheria protein toxin., wherein the protein has a binding- site mutation that reduces binding.
30. The immunotoxin of claim 29, wherein the immunotoxin comprises a mutant diphtheria toxin moiety linked to a single chain variable region antibody which routes by the anti-CD3 pathway, or derivatives thereof.
31. The immunotoxin of claim 30, wherein the immunotoxin is scUCHTl-DT390.
32. The immunotoxin of claim 30, wherein the
immunotoxin is an anti-Vβ-CRM9.
33. The immunotoxin of claim 30, wherein the
immunotoxin is an anti-Vα-CRM9.
34. An immunotoxin, wherein the immunotoxin
comprises a mutant diphtheria toxin moiety linked to a single chain variable region antibody which routes by the anti-CD3 pathway, or derivatives thereof.
35. The inununotoxin of claim 34, wherein the
diphtheria toxin moiety has a binding site mutation that reduces binding.
36. The immunotoxin of claim 34, wherein the immunotoxin is scUCHTl-DT390.
37. The immunotoxin of claim 34, wherein the immunotoxin is an anti-Vβ-CBM9.
38. The immunotoxin of claim 34, wherein the immunotoxin is an anti-Vα-CRM9.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT96913790T ATE460179T1 (en) | 1995-04-14 | 1996-04-12 | METHOD FOR ADDING IMMUNE TOLERANCE USING IMMUNOTOXINS |
| CA2218166A CA2218166C (en) | 1995-04-14 | 1996-04-12 | Methods of inducing immune tolerance using immunotoxins |
| EP96913790A EP0830146B1 (en) | 1995-04-14 | 1996-04-12 | Methods of inducing immune tolerance using immunotoxins |
| DE69638145T DE69638145D1 (en) | 1995-04-14 | 1996-04-12 | METHOD FOR IMPROVING AN IMMUNOTOLERANCE WITH THE HELP OF IMMUNOXINES |
| AU56637/96A AU5663796A (en) | 1995-04-14 | 1996-04-12 | Methods of inducing immune tolerance using immunotoxins |
| AU39405/00A AU762197B2 (en) | 1995-04-14 | 2000-06-12 | Methods of inducing immune tolerance using immunotoxins |
| US09/810,999 US7288254B2 (en) | 1995-10-30 | 2001-03-16 | Use of immunotoxins to induce immune tolerance to pancreatic islet transplantation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42210095A | 1995-04-14 | 1995-04-14 | |
| US08/422,100 | 1995-04-14 | ||
| US8810495P | 1995-10-30 | 1995-10-30 | |
| US60/088,104 | 1995-10-30 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US62874596A A-371-Of-International | 1995-10-30 | 1996-11-18 | |
| US87837897A Continuation | 1995-10-30 | 1997-06-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO1996032137A2 WO1996032137A2 (en) | 1996-10-17 |
| WO1996032137A3 WO1996032137A3 (en) | 1997-01-09 |
| WO1996032137B1 true WO1996032137B1 (en) | 1997-02-20 |
Family
ID=26778277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/005087 WO1996032137A2 (en) | 1995-04-14 | 1996-04-12 | Methods of inducing immune tolerance using immunotoxins |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0830146B1 (en) |
| AT (1) | ATE460179T1 (en) |
| AU (2) | AU5663796A (en) |
| CA (1) | CA2218166C (en) |
| DE (1) | DE69638145D1 (en) |
| WO (1) | WO1996032137A2 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7288254B2 (en) | 1995-10-30 | 2007-10-30 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services, Nih | Use of immunotoxins to induce immune tolerance to pancreatic islet transplantation |
| US7696338B2 (en) | 1995-10-30 | 2010-04-13 | The United States Of America As Represented By The Department Of Health And Human Services | Immunotoxin fusion proteins and means for expression thereof |
| US7517527B2 (en) | 1995-10-30 | 2009-04-14 | The United States Of America As Represented By The Department Of Health And Human Services | Immunotoxin with in vivo T cell suppressant activity and methods of use |
| US7125553B1 (en) | 1996-04-15 | 2006-10-24 | The United States of America as represented by the Department of Health and Human Services c/o Centers for Disease Control and Prevention | Methods of inducing immune tolerance using immunotoxins |
| CA2284079C (en) * | 1997-03-05 | 2009-05-12 | David M. Neville | Immunotoxins and methods of inducing immune tolerance |
| EP0968282A2 (en) * | 1997-03-05 | 2000-01-05 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Vectors and methods for expression of mutant proteins |
| AU768547B2 (en) * | 1999-01-08 | 2003-12-18 | Wisconsin Alumni Research Foundation | Methods of prolonging transplant survival using immunotoxins and costimulation blockade of CD154 and CD28 |
| EP1287147B1 (en) * | 2000-05-18 | 2009-12-16 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, represented by THE DEPARTMENT OF HEALTH & HUMAN SERVICES | Immunotoxin fusion proteins and means for expression thereof |
| US9125891B2 (en) | 2008-03-07 | 2015-09-08 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Lymph nodes as a site for regeneration |
| WO2014138486A1 (en) * | 2013-03-06 | 2014-09-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Lymph node as a site for transplantation, organogenesis and function for multiple tissues and organs |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4520226A (en) * | 1982-07-19 | 1985-05-28 | The United States Of America As Represented By The Department Of Health And Human Services | Treatment of graft versus host disease using a mixture of T-lymphocyte specific monoclonal antibody: ricin conjugates |
| US5167956A (en) * | 1991-02-11 | 1992-12-01 | The United States Of America As Represented By The Department Of Health And Human Services | Immunotoxin with in-vivo t cell suppressant activity |
| DK0616034T3 (en) * | 1993-03-05 | 2005-02-21 | Wyeth Corp | Plasmid for the preparation of CRM protein and diphtheria toxin |
-
1996
- 1996-04-12 CA CA2218166A patent/CA2218166C/en not_active Expired - Lifetime
- 1996-04-12 DE DE69638145T patent/DE69638145D1/en not_active Expired - Fee Related
- 1996-04-12 WO PCT/US1996/005087 patent/WO1996032137A2/en active Application Filing
- 1996-04-12 AT AT96913790T patent/ATE460179T1/en not_active IP Right Cessation
- 1996-04-12 AU AU56637/96A patent/AU5663796A/en not_active Abandoned
- 1996-04-12 EP EP96913790A patent/EP0830146B1/en not_active Expired - Lifetime
-
2000
- 2000-06-12 AU AU39405/00A patent/AU762197B2/en not_active Expired
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