Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1994-09-26
2001-01-09
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S131100, C530S387100, C530S387200, C530S389100
Reexamination Certificate
active
06171585
ABSTRACT:
The present invention relates to methods of transplantation. In a particular aspect, the invention relates to methods to immunosuppress a potential transplant recipient so as to be amenable to transplant with donor organs obtained from a variety of donors including histoincompatible donors. In another aspect, the present invention relates to methods to reduce the likelihood of rejection of a transplanted organ by a transplant recipient. In yet another aspect, the invention relates to methods to prolong the survival of a transplant recipient. In a further aspect, the invention relates to methods of transplantation which reduce the extensive immunosuppressive treatment post-transplantation.
BACKGROUND OF THE INVENTION
Although transplantation of organs is becoming commonplace, rejection of the donated organ by the patient remains a serious problem. Except for cases of organ donation between identical twins or the special instance of transplantation in individuals with severe combined immunodeficiency disease, all transplant recipients currently require an immunosuppressive regimen to prevent rejection. Although these immunosuppressive drugs are administered post-transplantation in an attempt to prevent rejection, they also suppress the body's defenses against infection. Thus, transplantation requires a continued effort to induce acceptance of the graft without paralyzing the body's immune system.
Various regimens in use employ one or more of the following agents or therapies: (1) corticosteroids, such as prednisone; (2) cytotoxic drugs, such as azathioprine and cyclophosphamide; (3) x-ray irradiation therapy; (4) anti-lymphocyte and anti-thymocyte globulins; (5) cyclosporine; and (6) monoclonal antibodies such as OKT3, which reacts specifically with the CD3 antigen-recognition structure of human T cells and blocks the T cell effector function involved in allograft rejection.
All of the above described therapy methods are administered post-transplant and have undesirable side effects. For example, corticosteroids may cause decreased resistance to infection, painful arthritis, osteoporosis, and cataracts. Cytotoxic agents may cause anemia and thrombocytopenia, and sometimes hepatitis. The antilymphocyte globulins may cause fever, hypotension, diarrhea, or sterile meningitis. Cyclosporine may cause decreased renal function, hypertension, tremor, anorexia, and elevated low-density lipoprotein levels. OKT3 may cause chills and fever, nausea, vomiting, diarrhea, rash, headache, photophobia, and occasional episodes of life-threatening acute pulmonary edema.
There are two types of allograft rejection, acute humoral rejection (hyperacute rejection) and acute cellular rejection (acute rejection). Hyperacute humoral rejection is generally an overwhelming, irreversible process that occurs when organs are transplanted into recipients who have preformed cytotoxic antibodies against antigens of the donor allograft, such as anti-HLA antibodies (i.e., immunohistoincompatibility). Up until now, no combination of immunosuppressive drugs has been capable of reversing or inhibiting this rapid hyperacute rejection process.
Intravenous gammaglobulin (IVIg) has been in use since 1981, primarily for prophylaxis in those with primary or secondary immunodeficiency states. Beneficial results have also been reported in the treatment of childhood idiopathic thrombocytopenic purpura, in CMV prophylaxis for bone marrow transplantation, amelioration of GVHD (graft versus host disease), and other autoimmune disorders. IVIg is known to contain antiidiotypic antibody activity against a number of autoantibodies (i.e., anti-ANA and anti-ANCA), but little is known about IVIg's antiidiotypic activity against alloantibodies. IVIg is known to block antibody response in vivo and in vitro although the exact mechanisms are not known. IVIg has been used successfully to obtain improved post transfusion platelet increments in refractory patients.
A wide source of donor organs are potentially available to various patients in need of a transplant. However, due to positive crossmatch that is typically observed between a highly sensitized organ-recipient and organ-donor, only a very small percentage of available donor-organs are actually suitable for transplant for any given potential organ-recipient. Thus, methods useful for increasing the percentage of donor-organs available to organ-recipient candidates are needed.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered that candidate transplant patients can be treated prior to transplantation so as to improve the likelihood of successful transplantation. The improvement is accomplished by increasing the likelihood of a negative crossmatch between the transplant recipient and the specific organ-donor. Thus, methods for transplanting an allograft in a patient are provided. Particularly, the present invention provides a method for preventing hyperacute rejection of a transplanted organ or tissue by a recipient mammal that includes the step of administering to a mammal, prior to the transplantation, an anti-HLA-antibody-depleting agent.
The invention methods are useful to expand the available source of donor organs which are acceptable for a given transplant recipient. The invention methods permit a highly sensitized or HLA sensitized patient to be successfully immunosuppressed in vivo and subsequently transplanted with a crossmatch negative, but histoincompatible, donor-organ. The present invention improves the prognosis of a transplant recipient for long-term survival (“actuarial graft survival”), and reduces the need for immunosuppressive treatment. The present invention prevents infection and does not add to the patient's immunosuppressive load, e.g., does not increase the risk of malignancy or infection. In addition, the invention method reduces the time that potential transplant candidates spend waiting for a compatible, crossmatch negative donor.
An pre-transplant assay for predicting which patients are amenable to treatment with the invention methods of transplantation is also provided. The pre-transplant assay also allows the determination of one or more residual anti-HLA antibody specificities remaining in the transplant candidate, which thus permits the determination and avoidance of a specifically defined population of donor-organs at transplant.
REFERENCES:
patent: 5200400 (1993-04-01), Teramoto et al.
patent: 5204329 (1993-04-01), Ackerman et al.
Peraldi et al., Transplantation, 1996, 62(11):1670.
Riggio, R.R., et al., “Enhanced Kidney Graft Survival With Retroplacental Source &ggr;-Globulin,”Transplantation, 23(6):636-641 (1982).
Auch N Cross in Transplantation Immunology CD. Bach and Auchin Cross, Wiley-Liss NY 1995 pp. 211-218.
1. Tyan et al. Transplantation 57: 553-562 (1994).
2. Riggio et al. Proc. Eur. Dial. Transplant. Assoc. 16:426 (1979).
Harris et al. TIBTECH, 11:42, 1993, Therapeutic. . . Age.
Sullivan et al., N. Eng. J. Med., 323:705, 1990, Immunomodulation. . . transplantation.
Clark et al., The Experimental Foundations of Modern Immunology, 1991, pp. 420-443.
Rodey et al., Transplantation, 1989, 48 (1): 54-57.
Buckley and Schiff, “The Use of Intravenous Immune Globulin in Immunodeficiency Diseases,”The New England Journal of Medicine 325:110-117 (1991).
Dwyer, “Manipulating the Immune System with Immune Globulin,”The New England Journal of Medicine 326:107-116 (1992).
Glotz, et al., Inhibition of Anti-HLA Antibodies (Ab) Cytotoxicity and Synthesis by Intravenous Polyclonal Immunoglobulins (IVIg), ASN Abstracts, Abstract No. 87P (1992).
Jordan and Tyan, “Intravenous Gamma Globulin (IVIG) Inhibits Lymphocytoxic Antibody Activity in Vitro,” Proceedings of the 24th Annual Meeting of The American Society of Nephrology (1991).
Kaveri et al., “Intravenous Immunoglobulins IVIg in the Treatment of Autoimmune Diseases,”Clin. Exp. Immunol. 86:192-198 (1991).
Lambrechts et al., “Mechanism of Allograft Tolerance in Nonhuman Primates: Purification of a Specific Isotype of IgG With Suppressor Activity,”Tr
Jordan Stanley C.
Tyan Dolly B.
Campbell & Flores
Cedars-Sinai Medical Center
Gambel Phillip
LandOfFree
IVIg immunosuppression in HLA-sensitized transplant recipients does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with IVIg immunosuppression in HLA-sensitized transplant recipients, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and IVIg immunosuppression in HLA-sensitized transplant recipients will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2546013