Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-08
2002-06-04
Ceperley, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S017400, C536S017600
Reexamination Certificate
active
06399578
ABSTRACT:
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
(Not applicable)
TECHNICAL FIELD
This invention relates to the field of xenotransplanation and immunotolerance. More specifically, it relates to conjugates of galactose &agr;1,3 galactosyl epitope(s) (&agr;Gal) for use in reducing levels of circulating anti-&agr;Gal antibodies and inducing immune tolerance to xenotransplanted tissue.
BACKGROUND
There is a large and increasing need for organ transplantation, which is exacerbated by a critical shortage of available human organs for transplant. The possibility of employing xenotransplantation to overcome the lack of human organs for allotransplantation is a possible solution to the critical organ shortage but in itself presents serious problems.
Two basic types of xenografts have been studied. In concordant xenografts, an organ from a donor animal is transplanted into a similar species which lacks antibodies to the donor organ. Rejection of a concordant organ is usually caused by T cell-mediated reactivity to differences in major histocompatability antigens. Concordant xenotransplantation had been applied to human patients as early as 1963 with the most celebrated case being the transplantation of a baboon heart into a human neonate. Auchincloss et al. (1998)
Ann. Rev. Immunol
. 16:433. In discordant transplants, the donor and recipient are phylogenetically more distant and the recipient has antibodies to the donor organ as is the case of porcine organs transplanted into Old World primates. These xenografts are rejected within the first few minutes due to the phenomenon of hyperacute rejection (HAR).
In humans and Old World primates, natural antibodies specific for the galactose &agr;1,3 galactosyl (&agr;Gal) epitope mediate both the hyperacute rejection (HAR) and delayed xenograft rejection (DXR) of organs xenotransplanted from animals such as pigs. Humans and Old World primates express high levels of circulating antibodies to galactose &agr;1,3 galactosyl (&agr;Gal) residues which are expressed at high levels on membrane lipids and proteins of other animal species. Galili et al. (1988)
J. Biol. Chem
. 263:17755. This is due to the fact that humans and Old World primates lack the enzyme &agr;1,3 galactosyltransferase which is required to express the &agr;Gal epitope (Sandrin et al. (1993)
Proc. Natl. Acad. Sci. USA
90:11391) and thus make antibodies to the &agr;Gal epitope which is expressed on normal gut flora and is recognized as foreign. By contrast, xenograft organ donor species (e.g., pigs) express the &agr;1,3 galactosyltransferase enzyme and thus express the &agr;Gal epitope. It has been estimated that there are approximately 10
7
&agr;Gal epitopes per cell on many donor tissue cells. Cooper et al. (1998)
Xenotransplantation
5:6-17.
When an &agr;Gal-expressing discordant organ is transplanted into a recipient that produces anti-&agr;Gal antibodies, the first deleterious result is HAR mediated by the high levels (up to 4% of circulating IgM) of the natural anti-&agr;Gal Ig. Parker (1994)
J. Immunol
. 153:3791. &agr;Gal bearing transplants (porcine islets) into humans have been shown to increase anti-&agr;Gal responses by up to 64-fold. Galili et al. (1995)
Transplantation
59:1549. Transplantation of pig cartilage into cynomolgus monkeys causes a 30-300 fold increase in IgG anti-&agr;Gal and 2-16 fold increase in IgM. Galili et al. (1997)
Transplantation
63:646. These natural antibodies bind to &agr;Gal expressed on the endothelial surfaces of the engrafted organ which both activates the complement system and the endothelium causing damage to the cell and sets up a net prothrombotic state on the vessel surface. The result is a damaged endothelium and massive clotting causing the rapid development of ischemia of the transplanted organ and its functional incapacitation within minutes to hours.
Anti-&agr;Gal antibodies also play a role in delayed xenograft rejection (DXR), the intermediate term (several days) damage to xenotransplanted organs which often results in rejection. Bach et al. (1995)
Nature Med
. 1:869-873. Anti-&agr;Gal antibodies bind to the endothelium and mediate a plethora of cell-mediated responses such as ADCC, leading to vascular and tissue damage which compromises the function of the transplanted organ. Anti-&agr;Gal antibodies can also cause chronic activation of receptors on xenograft cells and/or increased immunogenicity of xenograft-specific antigens. Cooper et al. (1998)
Xenotransplantation
5:6-17. Diminution of anti-&agr;Gal antibodies levels can attenuate this damage, but the damage, even if not acute, is cumulative and can eventually leads to organ rejection.
Various strategies have been pursued to deal with the major sequelae of anti-&agr;Gal antibody binding. These include: 1) inhibition of effector functions mediated, directly or indirectly by anti-&agr;Gal antibodies; 2) depletion of recipient anti-&agr;Gal antibodies; 3) sublethal irradiation and reconstitution of recipient with autologous and donor bone marrow; 4) modification of donor tissue glycosylation; 5) suppression of anti-&agr;Gal antibodies in recipient; and 6) administration of &agr;Gal moieties found on donor tissue to the recipient.
In attempts to inhibit the effector functions mediated by anti-&agr;Gal antibody binding, much effort has been spent to generate donor animals transgenic for complement regulatory proteins such as decay accelerating factor (DAF, CD55), and homologous restriction factor (HRF, CD59). Schmoekel et al. (1996) Transplantation 62:729; and Byrne et al. (1997)
Transplantation
63:149. These proteins, members of the regulators of complement activation (RCA) gene family, can downregulate the generation of complement proteins which mediate acute inflammation and cell lytic activity. Transgenic expression of RCA proteins does nothing, however, to address the effect of anti-&agr;Gal antibodies binding to the endothelium which sets up the net prothrombotic state subsequent to endothelial cell activation. Thus, while RCA-transgenic donor organs may have an ameliorative effect on HAR, this approach will not have an effect on DXR wherein xenograft damage is mediated by effector cells which bind to anti-&agr;Gal antibodies. Further, while the expression of RCA molecules on the transplanted organ may protect the transplant from protective functions of the host/recipient immune response, if the transplanted organ were to express pathogen antigens (from viral or bacterial infection), protective antibody effector function mediated by complement would be effectively shut off leaving the host with an organ full of pathogen-infected cells. For these reasons, strategies aimed at controlling complement are thought to be insufficient to achieve long-term graft survival unless acceptable regimens are developed to reduce antibody responses. Soulillou (1998)
Xenotransplantation
5:1-2.
Depleting the recipient of pathogenic anti-&agr;Gal antibodies has been shown to prolong pig organ survival. Cooper et al. (1996)
Xenotransplantation
4:27. However, attempts to remove the natural anti-&agr;Gal antibodies by apheresis have been only temporarily effective and result in an only slightly delayed antibody-mediated organ rejection. Pathogenic levels of anti-&agr;Gal antibodies return within 1-2 days and mediate xenograft damage. Sablinski et al. (1995)
Xenotransplantation
2:264; Cooper et al. (1998)
Xenotransplantation
5:6. Thus, very frequent ex vivo plasmapheresis to reduce the incidence of HAR would be required. Furthermore, the cumulative damage by levels of anti-&agr;Gal antibodies too low to mediate HAR but which mediate DXR are unavoidable using the plasmapheresis strategy. In addition, currently available pharmacological interventions, even in combination, only have modest effect in inhibiting anti-&agr;Gal antibody production. Cooper et al. (1998)
Xenotransplantation
5:6. Thus, it seems unlikely that permanent suppression of anti-&agr;Gal responses will be possible using this approach.
The use of mixed chimerism, wherein human organ r
Jack Richard M.
Jones David S.
Yu Lin
Ceperley Mary E.
La Jolla Pharmaceutical Company
Morrison & Foerster / LLP
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