Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
2000-06-09
2002-09-24
Lankford, Jr., Leon B. (Department: 1651)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C435S002000, C435S325000, C424S093730
Reexamination Certificate
active
06455306
ABSTRACT:
BACKGROUND OF THE INVENTION
A. Technical Field
This invention relates to a transfusable composition of cells produced by ex vivo growth processes. More particularly, it relates to transfusable compositions that are universally compatible, perform the same physiologic function as red blood cells (“rbcs” or “erythrocytes”) from human donors, and supplement or replace the current practice of transfusing red blood cells from human donors.
B. Background Art
1. Current Blood-Banking Practice
Blood transfusion is a critical component of current medical practice. Each year there are about 12 million donation units transfused in the United States. Of these, 3.2 million units are used to treat chronic anemia, 8 million units are used to treat surgical blood loss and about 750,000 units are used to treat traumatic blood loss. As practiced currently, blood transfusion involves drawing blood from a presumed healthy donor, mixing it with an anticoagulant/preservative, testing it for immunologic reactivity (typing), testing it for known infectious agents (currently eight) and storing it for administration to suitable recipient/patient. Prior to administration to the recipient, a sample of the donor blood is tested in combination with a sample of the recipient's blood to determine immunologic compatibility (cross-matching). After establishing compatibility, the donated blood is intravenously infused into the recipient. Despite the testing precautions, blood transfusions pose life-threatening risks to the recipient. Epstein,
Increasing Safety of Blood Transfusions, Amer
. Red Cross (1992).
Although there are recognized therapeutic applications for white blood cells, platelets and other components of blood, e.g. coagulation factors, plasma proteins. etc., the predominate use for blood transfusions is based on the oxygen-carrying ability of the red blood cells. A unit of whole blood is 500 milliliters or approximately one pint. Adults have from about 9 to about 12 pints of blood in their bodies. Blood donated for transfusion is typically composed of 40-50% (by volume) red blood cells and 50-60% plasma (liquid component). One milliliter of blood typically contains 4 to 5 billion rbcs, which is equivalent to 2.0 to 2.5 trillion rbcs per donation unit.
Blood typing is the process by which red blood cells are tested to determine which cell surface antigens are present and absent. It is standard blood-banking practice to test routinely for the A, B, and D (Rh) antigens and to test for other antigens only in selected cases. When a person lacks a particular red blood cell antigen, his or her plasma may contain an antibody to that antigen. Some antibodies (e.g. anti-A and anti-B) are naturally occurring and are expected to be present. Other antibodies are unexpected. They usually result from a challenge to the immune system by exposure to foreign blood cells, such as through transfusion or pregnancy. A small percentage of persons carry antibodies to certain blood cell antigens without prior exposure.
Antibody reactions with antigens present on infused red cells often result in a serious adverse clinical event known as a “transfusion reaction.” With the exception of the ABO blood group system, the kinds of antibodies that cause transfusion reactions are found almost exclusively in persons who have had prior transfusions or pregnancies. Antibodies in the patient's plasma are detected in screening studies using panels of red cells containing known antigens.
Blood group antigens are glycoprotein or glycolipid structures on the surface of the red cell membrane and can be removed or modified in potency by using various enzymes, e.g. glycosidases, proteases, etc. Red cell antigens vary in their immunogenicity and prevalence.
In routine blood-banking practice, only ABO typing and Rh grouping are performed. A crossmatch procedure is performed as a final check for compatibility.
Crossmatching is performed by mixing the donor's cells with the recipient's serum, with and without enhancing agents, and observing for agglutination (clumping) or lysis (destruction) of the red cells. Either of these events signals that a problem antibody to an antigen on the donor's cells is present in the recipient's plasma and signals the likelihood of a transfusion reaction.
The frequency and identity of problem antibodies/blood types have been established (in order of decreasing frequency):
1. Anti-D (with or without anti-C or anti-E);
2. Anti-Le
a
and anti-Le
b
(alone or together);
3. Anti-K;
4. Anti-E anti-P
1
;
5. Anti-c, Anti-cE, Anti-Fy
a
, Anti-M;
6. Anti-jK
a
, Anti-S;
7. Anti-Ce, anti-E;
8. Anti-jK
b
, anti-N, Anti-s. anti-Fy
b
.
Because of a variable and uncertain supply (often critical shortages), the potential for transmitting blood-borne disease, and the risk of immunologic incompatibilities and transfusion reactions, there is a recognized and substantial need to supplement or replace the current practice of transfusing blood from human donors.
2. Ex Vivo Cell Culture
Mature blood cells result from the growth and differentiation of hematopoietic cells. Hematopoietic cells are generated from pluripotent stem cells, which can both self-renew and give rise to hematopoietic progenitor cells. Hematopoietic progenitor cells include lymphoid, mixed-lineage colony-forming units (CFU-Mix), granulocyte/macrophage colony-forming units (CFU-GM), erythrocyte burst-forming units (BFU-E), and megakaryocyte burst-forming units (BFU-meg). These progenitors, in turn, give rise to mature blood cells. (Koller et al.,
Biotechnol. Bioeng
. 42: 477 (1993).
Primitive hematopoietic cells reside in the bone arrow of normal adults, where they mature into functional blood cells and are released into the peripheral circulation. The bone marrow is a complex environment consisting of stem, progenitor and mature hematopoietic cells, along with accessory cells and molecules (in extracellular matrix) which are necessary to maintain the process of hematopoiesis. Accessory cells and the extracellular matrix mediate the differentiation and proliferation of hematopoietic cells by producing growth factors and by direct cell contact. Bone marrow, thus, is a natural source of hematopoietic cells at various stages of differentiation, as well as a source of accessory cells. Immature hematopoietic cells can also be harvested from peripheral blood, with or without stimulation by growth factors, using leukopharesis. This process separates the nucleated cells of interest from red blood cells and plasma. Another source of immature hematopoietic cells is umbilical cord blood. Bone marrow has been the traditional source of hematopoietic cells for transplantation therapies, although peripheral blood progenitor cell transplants have also proven useful. Demuynck, et al.,
Ann. Hematol
. 71: 29 (1995).
Cancer chemotherapy often results in severe damage to hematopoietic progenitor cells. As a result, the patient is susceptible to infection and bleeding. A therapy for this damage involves transplantation of bone marrow or hematopoietic cells. The loss of hematopoietic activity, due to damage by chemotherapy, can be offset by infusing hematopoietic cells into the patient after chemotherapy. Thus, there has been much interest and in harvesting and expanding hematopoietic progenitor cells in ex-vivo cell cultures.
Ex vivo expansion of hematopoietic progenitor cells can decrease the amount of the initial harvest necessary for successful engraftment and, most importantly, can improve the transplant outcome by allowing more cells to be transplanted. Such expansion supplements transplants with mature progenitors and speeds the recovery of mature white cells and platelets, which in turn fight infection and control bleeding, respectively. In addition, ex vivo expansion also allows the use of a single hematopoietic cell harvest for repeated transplants over an extended period of time. Collins. et al.,
Curr. Opin. in Biotechnol
., 7: 223 (1996).
Ex vivo expansion of hematopoietic cells includes the following prerequisites: First, cells positive for th
Goldstein Walter Elliott
Miller Warren Keene
Lankford , Jr. Leon B.
Rothwell Figg Ernst & Manbeck
Transcyte, Inc.
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