Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1998-04-06
2001-10-09
Chan, Chrstina Y. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S093700, C424S520000, C435S325000, C514S885000, C514S054000, C536S001110
Reexamination Certificate
active
06299878
ABSTRACT:
FIELD OF INVENTION
The invention relates to the production of compositions, particularly pharmaceutical compositions, containing one or several active principles capable of controlling the immune reactions of a host against allogeneic or xenogeneic cells, tissues or organs or of immuno-competent cells against an immuno-incompetent or immuno-suppressed host, particularly those immune reactions which are involved in the so-called host versus-graft reaction (HvGR) and so-called graft versus-host reaction (GvHR) or graft versus-host disease (GvHD), as well as immune reactions which are brought into play in bone marrow transplantation (BMT), i.e. when the host is transplanted with allogeneic or xenogeneic incompatible bone marrow.
DESCRIPTION OF THE RELATED ART
Series of studies have been initiated in 1978 by one of the inventors relative to the bone-marrow-engraftment-promoting activity of bone-marrow-derived factors (Pierpaoli W. et al, Transplantation 1978; 26: 456-458) and (Pierpaoli W. et al, J. Clin. and Lab. Immunol. 1985; 16:115-124). The initial observation was that the supernatant of a solution in which the bone marrow cells had been suspended (bone marrow supernatant: BM-SN) provided an engraftment-enhancing activity (Pierpaoli W. et al, Cell Immunol 1980; 52:62-72). This indicated the presence of factors able to modify the capacity of the bone marrow to be engrafted in an irradiated host for induction of permanent allogeneic or xenogeneic chimerism.
An extensive series of experiments further demonstrated that high-molecular-weight fractions obtained by ultrafiltration through porous membranes of the native BM-SN derived from rabbit marrow contained marrow-regulating factors (MRF) capable of exerting the same effect, i.e., of inducing hemopoietic chimerism across the H-2 barrier in the murine model (Pierpaoli W. et al, Cell Immunol 1981; 57:219-228). However, the results obtained were not easily reproduced, at least quantitatively; there was considerable variability in the results and the incidence of secondary disease was high. Moreover, induction of chimerism was not achieved in all of the murine H-2 combinations tested (Pierpaoli W. et al, J Lab Clin Immunol 1985; 16:115-124).
European Patent application n° EP89403103.8/0426924 Pierpaoli W. et al, Cell Immunol 1981;57:219-228 and Pierpaoli W. et al, J Lab Clin Immunol 1985;16:115-124) reported that a specific component from rabbit bone-marrow-derived fractions, namely transferrin, could be responsible for the facilitation of allogeneic and xenogeneic bone marrow engraftment that had been achieved earlier with rabbit and bovine, marrow-derived fractions. Treating lethally irradiated C57BL/6 mice transplanted with bone marrow from BALB/c donors with iron-saturated human transferrin or conalbumin, resulted in remarkably stable engraftment, avoidance of GvHD and enduring chimerism in the majority of test animals (Pierpaoli W. et al, Cell Immunol 1991;134:225-234).
Transferrins as such have been abundantly studied. They consist of two-sited, single-chain proteins capable of binding metals. They are widely distributed in physiological fluids and cells of vertebrates.
Each of the transferrin molecules consists of a single polypeptide chain, of molecular weight in the range 76,000-81,000, which contains two similar but not identical iron binding sites. Human serum transferrin contains about 5% carbohydrate, linked to the protein in two identical and nearly symmetrical branched heterosaccharide chains. It has a molecular weight of about 80,000. 1 mg of the iron-saturated protein contains about 1.4 &mgr;g iron.
The complete amino acid sequence of human plasma transferrin has recently been established by at least three groups using CNBr cleavage (CNBr) and by complementary DNA (cDNA) methods (MacGillivray, R. T. A., et al. “The complete amino acid sequence of human serum transferrin”. Proc. Natl. Acad. Sci. USA 79: 2504-2508, 1982 and Uzan, G. et al. “Molecular cloning and sequence analysis of cDNA for human transferrin. Biochem. Biophys. res. Commun. 119: 273-281, 1984 and Yang, F. et al. “Human transferrin: cDNA characterization and chromosomal localization”. Proc. Natl. Acad. Sci. USA 81: 2752-2756, 1984). It is composed of 678 amino acid residues, which together with the two-N-linked oligosaccharide chains exhibit a calculated molecular weight of 79,570 (of which 6% is contributed by the glucosidic moiety: MacGillivray, R. T. A. et al. and Uzan G. et al., “Molecular cloning and sequence analysis of cDNA for human transferrin”. Biochem. Biophys. Res. Commun. 119:273-281, 1984). Wiliams J. (“The evolution of transferrin”, Trends Biochem. Sci, 7: 394-397, 1982) has suggested the importance of sulfhydryl groups in stabilizing the iron-binding site and has traced their evolutionary development to the 17 disulfides found in human transferrin.
For a general review of the status of general knowledge about transferrins see the general publication titled “The Physiology of Transferrin and Transferrin Receptors” by Helmut A. Huebbers and Clement A. Finch in Physiological Reviews, vol. 67, No. 2, April 1987. That publication discloses also procedures for obtaining transferrin. Particularly transferrin of human origin in a biologically pure state has been disclosed in that publication. Preferred purification procedures are based on physicochemical separation steps followed by selective fixation on matrix-bound antibody or matrix-bound receptor.
Purified iron-saturated transferrin in a substantially biologically pure state, is substantially free of serum albumin proteins.
While the capability referred to above of iron-saturated human transferrin to protect lethally irradiated C5713L/6 mice recipients transplanted with bone marrow from BALB/c mice donors has been demonstrated, the engraftment-promoting activity of human transferrin in other H2-incompatible murine combinations was not as successful in all instances.
Human transferrin induced no immune tolerance in C57BL/6 mice grafted with marrow from C3H/He donors. Further work let the inventor to then consider that the promoting effects of transferrin rather varied according to the histogenetic H-2-type combination used, the promoting effect being maximal in C57BL/6 mice (H-
2b
) grafted with BALB/c (H-2
d
) marrow and absent in C57BL/6 mice grafted with C3H/HE (H-2
k
) marrow (Pierpaoli W. Nat. Immun. 1992; 11:356-365).
Thus it appears that the capability of plasma-derived transferrins (Tf) to profoundly affect engraftment of allogeneic or xenogeneic bone marrow in lethally irradiated mice and to produce a lasting chimerism, depends on a matching at least to some degree of the donor's transferrins and the cell and tissue antigens in the immunosuppressed and transplanted host. Indeed an induction of a durable state of immunological unresponsiveness or “tolerance” and, accordingly, a facilitation of engraftment of donor xenogeneic or allogeneic antigens, e.g., bone marrow, in irradiated or chemically immunosuppressed recipients treated with transferrin of a same donor is obtained, when said recipients are administered with the donor's transferrins and antigens, simultaneously or sequentially. A properly timed presentation of both transferrin and antigens, e.g., human transferrin and human leukocytes in immunosuppressed mice during initial recovery of their immune tissues and cells, results later in their inability to “recognize” human donor lymphocytes and to mount an immediate- or a delayed-type immune response against the antigens of the corresponding human donor. This “tolerant” state of the recipient mice has been confirmed by the absence of cytotoxic antibodies in the “tolerant” mouse sera against the human donor lymphocytes, by the inability of “tolerant” mice to mount a cell-mediated immune reaction in vivo against human donor leukocytes, and finally by an in vitro lack of reactivity of splenocytes of the “tolerant” mouse towards irradiated human donor lymphocytes. In summary, a donor's blood plasma-derived transferrin have the remarkable capacity of inducing a state
Kistler Gonzague S.
Pierpaoli Walter
Birch & Stewart Kolasch & Birch, LLP
Cellena AG
Chan Chrstina Y.
VanderVegt F. Pierre
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