Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-06-14
2003-04-01
Gambel, Phillip (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C435S326000, C435S332000, C435S334000, C435S343000, C435S343100, C435S343200, C435S346000
Reexamination Certificate
active
06541611
ABSTRACT:
This invention relates to an antibody (or fragment or derivative thereof) and preferably, to an antibody (or fragment or derivative thereof) which binds to human lymphocytes. More particularly, this invention relates to preventing and/or inhibiting on-going immune responses in a patient through the administration of such antibody (or fragment or derivative thereof) to a patient. Preferably, this invention relates to preventing or inhibiting T cell activation and proliferation through the administration of such antibody or fragment or derivative thereof to a patient.
The establishment of donor-specific immunological tolerance to primarily vascularized allografts would obviate the use of chronic immunosuppressive drug therapy and the associated morbidity and mortality. The main hurdle in developing tolerance protocols for use in humans is to determine the least toxic but consistently successful immunosuppressive regimens. It is therefore of overwhelming importance to establish experimental models, especially large animal models which will reliably be predictive of use in the clinical setting. Outbred primates seem to be the most appropriate clinical relevant model, and central tolerance induction to primarily vascularized renal allografts has. been previously reported in cynomolgus monkeys. (Kawai, et al.,
Transplantation
, Vol. 59 pg. 256 (1995); Kimikawe,
Transplantation
, Vol. 64, pg. 709 (1997)). Tolerance induction in this model was based on development of mixed hematopoietic chimerism and was obtained by concomitant donor bone marrow infusion, non-myeloablative total body irradiation (3 Gy) and an immunosuppressive regimen including transient injection of rabbit anti-human thymocyte globulins and cyclosporin. Other models of tolerance induction in primates including post-transplant transient depletion of peripheral T cells with rabbit anti-thymocyte globulins and subsequent infusion of donor bone marrow and total lymphoid irradiation have been reported. (Carver, et al.,
Transplant Proc
., Vol. 23, pg. 480 (1991)). Mixed chimerism seems to be the key for central tolerance induction, but devplopment of microchimerism requires, at least, non lethal myeloablative irradiation combined with T cell-depleting agents, as tolerance seems to be favored by a milieu with minimally reactive T cells. (Contreras, et al.,
Transplantation
, Vol. 65, pg. 1159 (1998)). The use of high doses of total irradiation in the clinical setting is, however, hazardous, especially in children, and efforts must be made in order to establish immunosuppressive protocols using easily monitorable T cell-depleting reagents that result in central tolerance and microchimerism as previously discovered in rodent studies. (Sykes, et al.,
Nature Medicine
, Vol. 3, pg. 783 (1997)).
Recent studies showed that tolerance to primarily vascularized allografts in primates might be induced without irradiation, by using a new anti-CD3 immunotoxin (Contreras, et al. 1998). This very powerful T-cell depleting agent was used in conjunction with donor lymphohematopoietic cell infusion in order to produce a high level of chimerism (Contreras, et al. 1998; Knechtle, et al.,
Transplantation,
Vol. 63, pg. 1 (1997); Thomas, et al.,
Transplantation
, Vol. 64, pg. 124 (1997)). The profound and long-lasting T-cell depletion in both peripheral blood and lymph nodes may, however, limit its clinical applicability. In addition, the pre-existence of an immune agent against the diphtheria toxin moiety of the anti-CD3 immunotoxin could reduce the efficiency of this agent. Nonetheless, this molecule clearly demonstrates that central tolerance induction might be achievable in primate models without total body irradiation.
As of this time, there are no available immunosuppressive agents other than anti-CD3 immunotoxin which might produce such a strong peripheral and lymphoid T cell depletion in humans. Nonetheless, the Campath-1 mAb has been used in human clinical trials for bone marrow transplantation and provided a high incidence of mixed chimerism and encouraging results have been reported in renal allografts using this mAb. (Friend,
Ann. Acad. Med. Singapore
, Vol. 20, pg. 503 (1991); Nagler, et al.,
Bone Marrow Transplantation
, Vol. 18, pg. 475 (1996); Friend, et al.,
Transplantation
, Vol. 48, pg. 248 (1989); Hamilton, et al.,
Bone Marrow Transplantation
, Vol. 17, pg. 819 (1996)). Recently, another mAb (LO-CD2a/BTI-322) has shown interesting T cell-depleting effects in humans. LO-CD2a/BTI-322, which is an anti-human CD2 mAb has demonstrated great efficiency in preventing acute cellular rejection in renal transplantation (Mourad, et al.,
Transplant. Proc
., Vol. 29, pg. 2353 (1991)), in graft versus host disease and liver transplantation (manuscript in preparation). This mAb, however, does not react with primate T cells, except for human and chimpanzee T cells and therefore cannot be used in experiments involving baboons and cynomolgus monkeys.
DETAILED DESCRIPTION
In accordance with the present invention, there is provided a monoclonal antibody or fragment thereof that recognizes both baboon and human CD2+ cells. As the CD2 molecule is expressed on all subsets of T cells including CD2 natural killer (NK) cells, LO-CD2b may be used as an immunotherapeutic reagent as well as providing a powerful tool for studies on optimizing conditioning regimens.
More particularly, in accordance with an aspect of the present invention, there is provided a molecule (preferably a monoclonal antibody or fragment thereof) which binds to the same epitope (or a portion thereof) on human lymphocytes as the monoclonal antibody produced by the cell line deposited as ATCC Deposit No. PTA-802. The antibody which is produced by the deposited cell line is hereinafter sometimes referred to as LO-CD2b. The term “molecule” or “antibody that binds to the same epitope as LO-CD2b” includes LO-CD2b. The term “LO-CD2b” includes the antibody produced by the deposited cell line and those identical thereto which may be produced, for example, by recombinant technology.
The molecules or antibodies of the present invention inhibit human T-cell activation and proliferation and Applicant has found that such inhibition can be effected when adding the molecule or antibody either before or after an agent which stimulates T-cell activation.
The molecules or antibodies of the present invention have the characteristics of binding to an epitope of a CD2 antigen (CD2 positive human T-cells) but it is to be understood, however, that the ability of such molecules or antibodies to inhibit T-cell activation or proliferation may or may not be effected through binding to CD2 positive cells, although Applicant presently believes that the mechanism of action involves binding of the molecule or antibody to CD2 positive cells.
In accordance with another aspect of the present invention there is provided a method of preventing and/or inhibiting on-going immune response in human patients through the administration to the patient of an antibody, hereinafter referred to as LO-CD2b (or fragment or derivative thereof) or any molecule that mimics such antibody or derivative or fragment thereof.
A cell line which produces LO-CD2b, was deposited on Jun. 22, 1999, at the American Type Culture Collection, 10801 University Blvd., Manassas, Va. 20110-2209, and was given the ATCC accession number PTA-802. Such antibody is a rat monoclonal antibody.
Although Applicants do not want to limit the invention to any theoretical reasoning, it is believed that the mechanism which enables the monoclonal antibody of this invention to prevent or reduce the severity of an immune response, and to inhibit the activation and proliferation of T-cells, is the fact that the LO-CD2b antibody either decreases the density of CD2 expressed on T cell surfaces and thus decreases the number of CD2
+
T lymphocytes; and/or affects signal transduction. It is believed that these mechanisms of action are responsible for not only the prevention of immune response, but also the reduction in severity of on-going immune respo
Bazin Herve
Gianello Pierre
Latinne Dominique
Gambel Phillip
Lillie Raymond J.
Olstein Elliot M.
Universite Catholique de Louvain
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