Method for increasing mean survival times of transplants...

Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C424S130100, C424S143100, C424S144100, C424S153100, C424S173100, C530S387100, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750

Reexamination Certificate

active

06214342

ABSTRACT:

The present invention relates to the use of monoclonal antibodies for the preparation of a medicinal product for preventing the rejection of transplants of solid organs, to medicinal products comprising them and to a medical kit for effecting this prevention. Solid organs are understood to mean, in particular, the kidney, heart, lungs, liver and skin, an well as endocrine glands such as pituitary glands, thyroid and pancreas and cell suspensions extracted from these (for example islets of Langerhans), and the like.
The last decade has seen an improvement in the results of organ, in particular, kidney, transplantations, reflected in an improvement in the survival of the patients and of the grafts. Before 1981, the use of azathioprine (AZA) and of prednisone (P) constituted the means of primary prophylactic immunosuppression in relation to renal transplantation, despite a relatively low rate of survival of the graft. The appearance of cyclosporin A (CsA) enabled graft survival to be significantly improved, approximately 90% surviving at one year (in “Annual Report of United Network for Organ Sharing” 1989, UNOS Eds. Richmond—J. M. Ceaka et al., The UNOS scientific renal transplant registry, in “Clinical transplants” 1989: 1-8 UCLA Eds. Los Angeles), with a prolonged survival of the patients (approximately 95% in a one-year period), but with not-insignificant problems of toxicity an a counterpart. Polyclonal and monoclonal antilymphocyte antibodies have also been included in protocols of prophylaxis and curative treatment of rejection.
It has been possible to show low rates of early graft rejection by a two-stage treatment comprising initially the use of polyclonal antilymphocyte antibodies and than of CsA as principal maintenance immunosuppressant (A. J. Richardson at al., Transplant Internat 1990; 3: 26-31—B. G. Sommer et al., Transplantation 1987; 43: 85-90).
The introduction of monoclonal antibodies (mAb) having defined Specificity has made it possible to envisage a more precise action in term of induction of immunosuppression and treatment of rejection episodes. At the present time, only the antibody OKT3 (anti-CD3 mAb) has received a marketing authorization for the curative treatment of renal transplant rejection episodes (Ortho-clone OKT®3, Product Information, Physicians' Desk Reference, 43rd edition (Medical Economics Company Inc., N. J. Oradell, 1989, pages 1500-1501). However, only limited evidence of its efficacy in preventing kidney transplant rejection (in combination with a chemical immunosuppression) is available. For the moment, no monoclonal antibody has been recognized for this indication.
The LFA-1 molecule (lymphocyte function-related molecule) in an integrin which belongs to the lymphocyte adhesion complex involved in the phenomena of cellular adhesion and intercellular communication and which enhances, in particular, interactions between helper lymphocytes and their target cells. This family of products includes the Mac-1, LFA-1 and Gp150,95 molecules which possess a common beta chain of 95 kD and differ from one another in their alpha chain. The LFA-1 or CD11a/CD18 protein is a dimer of 180 kD present at the surface of bone marrow cells (leucocytic lines), T lymphocytes, NK cells, polymorphonuclear leucocytes and macrophages/monocytes. In vitro, monoclonal antibodies directed against LFA-1 inhibit most of the activities of T cells.
Anti-LFA-1 antibody has been used in children for the transplantation of HLA-incompatible bone marrow (A. Fischer et al., Lancet 1986; ii, (8515): 1058-1061—N. Perez et al., Bone Marrow Transplant 1989; 4: 379-384). Anti-LFA-1 antibodies have also been used in adult leukaemia patients for preventing an HLA-induced T cell-depleted bone marrow transplant rejection (D. Maraninchi et al., Bone Marrow Transplant 1989; 4: 147-150). They have also been used to treat 10 patients displaying an acute graft-versus-host reaction resistant to steroid treatments (A. M. Stoppa et al., Transplant Int. 1991; 4: 3-7).
In relation to renal transplantation, anti-LFA-1 monoclonal antibodies have been used in seven patients for treating episodes of acute transplant rejection (B. Le Mauff et al., Transplantation 1991; 52 (2); 291-296). The antibody used was the monoclonal antibody designated 25.3. Tolerance was good in the six patients who received more than one administration of this antibody. Infections were reported in two patients. However, only one patient, probably the one who experienced the weakest episode of rejection, regained his renal function before rejection, and a back-up treatment had to be instituted in five of them. In conclusion, this antibody was considered to be ineffective for treating the acute rejection occurring in the course of kidney transplantation. Use in the prevention of rejection has not been studied.
P. J. Berlin et al., Transplantation, Vol. 53, No. 4, 1992, Baltimore Md., USA, have described some degree of efficacy of the administration of anti-LFA-1 antibody for blocking the activity of T cells during the rejection of a cutaneous allograft in monkeys, and a slight prolongation of the survival of the graft before rejection. The only graft surviving at three months corresponds to a treatment combining an anti-CD11 and an anti-CD2.
Monoclonal antibodies directed against ICAM-1, the natural ligand for LFA-1, have shown some results in kidney transplant rejection in primates (B. A. Cosimi et al., Leukocyte Adhesion Molecules 1989: 274). The authors suggest that a treatment combining anti-ICAM-1 and anti-LFA-1 antibodies might be more effective (B. S. Cosimi et al., J. of Immunol., 1990, vol. 144, No. 12, 4604-4612).
M. Isobe, Proceedings of Int. Congress of Immunol. Budapest, Aug. 23-28, 1992 (Ed. Hungarian Soc. for Immunol.) Springer, Berlin, 1992, 554, W-90-19, also suggests a synergistic effect of anti-ICAM-1 and anti-LFA-1 monoclonal antibodies in allograft tolerance in rodents.
The prior art, while recognizing some useful properties in anti-LFA-1 antibodies, does not therefore suggest the use of these antibodies for preventing the rejection of transplants of solid organs, except in the form of combinations with other antibodies also involved in cellular adhesion phenomena.
The Applicant has now found that it was possible to prevent the rejection of transplants of solid organs, such as the kidney, by the administration of monoclonal antibody directed against the human LFA-1 (CD11a/CD18) molecule, this being achieved without combination with other antibodies or with cyclosporin A.
He also found that the efficacy of this use was greatly dependent on the implementation of a novel administration protocol.
The subject of the present invention is hence the use of monoclonal antibodies directed against the human LFA-1 molecule for the preparation of a medicinal product intended for the primary treatment for preventing the rejection of transplants of solid organs, in particular the kidney, in man. The monoclonal antibodies are preferably directed against the alpha chain of the LFA-1 molecule.
For the purposes of the present invention, antibodies are understood to mean human antibodies, non-human, for example murine, humanized, chimeric recombinant antibodies or other antibodies, as well as antibody derivatives, fragments and the like. All these antibodies, including the derivatives, may be prepared by standard methods.
The monoclonal antibodies which are useful in the invention may be characterized in that they react with:
T and B lymphocytes, monocytes, macrophages and polymorphonuclear leucocytes;
approximately 60% of thymocytes and prothymocytes;
T cell lines (for example MOLT-4, HPB-ALL and CEM lines);
the KG1 line, isolated from an acute myeloid leukaemia.
The monoclonal antibodies according to the invention have it as their objective to block the LFA-1 molecule and thus to reduce intercellular interactions. The monoclonal antibody should inhibit adhesion and the effector functions of T cells and NK cells.
Apart from the properties of binding, defined above, with the different cell classes, the monoclonal antibodi

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Method for increasing mean survival times of transplants... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for increasing mean survival times of transplants..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for increasing mean survival times of transplants... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2494567

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.