Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1992-06-23
1998-11-03
Eisenschenk, Frank C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
4353201, C12N 1513
Patent
active
058310630
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel monoclonal anti-RhD antibodies prepared by recombinant DNA methods.
The Rhesus blood group system is a major antigenic constituent of the human red blood cell membrane; of this group, the RhD antigen is of particular clinical importance in relation to isoimmune reactions. An Rh D-individual with anti-RhD who receives RhD+ blood is liable to suffer substantial red blood cell (RBC) destruction due to the RhD phenotype incompatibility, and thus blood of donors must routinely be classified as RhD+ or RhD-. Anti RhD monoclonal antibodies (anti-D Mabs) are capable of providing blood-typing reagents of high specificity and reliability.
The RhD antigen is also responsible for haemolytic disease of the newborn (HDN). This condition arises in newborn RhD+ infants of RhD- mothers previously sensitised to RhD Antigen as a result of IgG anti-RhD antibodies crossing the placenta during pregnancy and causing foetal red blood cell (RBC) destruction. Sensitization of the RhD- mother to RhD antigen often occurs during the birth of an earlier RhD+ child due to some foetal RBCs entering the maternal circulation and being recognised as foreign by the maternal immune system. To reduce the incidence of HDN, it is routine practice in the United Kingdom and many other countries to give anti-RhD antibodies to RhD- mothers immediately after the birth of an RhD+ infant so that any RhD+ RBCs which may have entered the maternal circulation are rapidly removed.
The search for the most effective anti D Mabs has proved to be extremely time consuming, involving the isolation of B-lymphocytes from humans immunised against RhD, usually Rh-ve mothers who have given birth to Rh+ve children. Such lymphocytes are subjected to EBV treatment to provide an immortalised cell-line directly or the EBV-treated cells are hybridised with suitable mouse myeloma cells to provide a hydridoma: The cell-line line or hybridoma may then be used to produce the anti-D Mab in the conventional way.
However, there are significant differences between anti-D Mabs in terms of their binding affinities for red cells, their ability to recognise D-variants such as D.sup.u and D.sup.VI, and their ability to destroy target cells by phagocytosis or cell-mediated lysis. It is desirable, therefore, to have available a method of combining the favourable parameters of different anti-D Mabs or, indeed of combining the most favourable features of selected anti-D Mabs with Mabs of quite different specificities which present particular advantages, in order to produce so-called chimaeric Mabs.
The concept of building chimaeric Mabs, has been described by Jones et al (Nature 321, 522-525 (1986)) and Riechmann et al (Nature 332, 323-327 (1988)). Three dimensional studies have shown that immunoglobulins comprise essentially constant regions common to most Mabs and terminally situated variable domains associated with antigen binding.
It has been shown that the variable domains consist of two .beta.-sheets joined by a disulphide bridge with their hydrophobic faces in contact. Sequence comparisons among heavy- and light-chain variable domains (V.sub.H and V.sub.L respectively) have revealed that each of these domains comprises three hypervariable domains or complementarity determining regions (CDRs) set in a framework of four relatively conserved regions, the framework regions (FRs). The CDRs are primarily responsible for the recognition of specific antigens. The structure of the .beta.-sheet framework is similar in different antibodies, as the packing together of V.sub.L and V.sub.H FRS is conserved and therefore the orientation of V.sub.L with respect to V.sub.H is fixed.
Genes coding for a number of Mabs are now available and the sequences coding for the variable regions V.sub.L and V.sub.H have been determined. It is thus possible to replace the latter sequences by DNA coding for V.sub.L and V.sub.H from different Mabs and indeed to construct the latter by incorporating DNA coding for chosen CDRs into DNA coding for a standard set of FRs. It is thus possi
REFERENCES:
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Eisenschenk Frank C.
National Blood Authority
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