Enzymatic Process
All human red blood cells have similar carbohydrate chains emitting from their surfaces that form a basic structure of the human blood group antigens. Except in extremely rare cases, all of these particular carbohydrate chains found on red blood cells have a specific sugar known as L-fucose attached to their terminal ends. A carbohydrate chain with an L-fucose sugar attached forms an assembly known as the H structure. In turn, the H structure provides the antigenic definition of group O red blood cells. In other words, the H structure forms the group O red cell antigen. When no other sugars are attached to the end of the H structure assembly, such red blood cells are defined as group O. With very rare exceptions, the H structure is found on all human red blood cells.
The creation of the H structure, i.e., the assembly of a carbohydrate chain and an L-fucose, occurs in the presence of a specific gene known as the H gene. Once the H structure is created it provides a foundation, or substrate, for the attachment of other sugars. In addition to the H gene, A and B genes may also be present. In the presence of an A gene, an additional sugar known as N-acetyl-D-galactosamine (GalNAc) is formed and attached to the H structure converting it to the group A antigen that defines group A red blood cells.
In the presence of a B gene, a sugar known as D-galactose (Gal) is formed and attached to the H structure converting it to the group B antigen thereby making group B red blood cells. When both A and B genes are present, some H structures are converted to A and some to B, thereby producing group AB red blood cells.
Antigen Removal
Since all A and B blood group specificities are built on group O (the H structure), it was reasoned that this could be reversed by the in vitro (outside the body) treatment of A and B red blood cells with specific enzymes that would separate, or cleave, the A and B terminal sugars from the H structure, thereby converting the A or B cells to group O red blood cells. (For purposes of this discussion, an enzyme is a protein that functions as a catalyst, i.e., a material which causes a reaction that results in the alteration of existing substances or the formation of a new substance.)
The immunodominant parts of A and B antigens are single sugar residues, N-acetylgalactosamine for A and galactose for B. Enzymes that are able to cleave these sugar residues specifically and selectively, termed glycosidases, exist in nature. Glycosidases of this type are small soluble proteins that can be produced cost effectively in sufficient quantities by modern gene technology in a form suitable for use in the clinical environment. The basic scientific concept was to identify specific glycosidases able to cleave the terminal sugars from the H structures on groups A, B and AB red blood cells. Implicit in this challenge was the requirement that neither the process nor the enzyme used to cleave either GalNAc or Gal could alter the H structure substrate or disrupt the red cell membrane. Additionally, the treatment process for converting red cells must maintain normal red cell integrity, viability and function such that the converted O or O-like cells are expected to function normally in vivo subsequent to transfusion.
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