Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1989-07-03
1993-06-15
Lacey, David L.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
5303871, 5303911, 5303915, 424 858, 424 8591, 435 696, 435 7021, 4351722, 4351723, 43524027, 4353201, C07K 1528, A61K 39395, C12P 2108
Patent
active
052199967
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an altered antibody molecule having therein a specific thiol group for use in attachment to the antibody molecule of effector or reporter molecules and to a process for its production using recombinant DNA technology.
In the present application:
the term "MAb" is used to indicate a monoclonal antibody;
the term "recombinant antibody molecule" (RAM) is used to describe an antibody produced by any process involving the use of recombinant DNA technology, including any analogues of natural immunoglobulins or their fragments; and
the term "humanised antibody molecule" (HAM) is used to describe a molecule having an antigen binding site derived from an immunoglobulin from a non-human species, the remaining immunoglobulin-derived parts of the molecule being derived from a human immunoglobulin. In a HAM the antigen binding site may comprise either complete variable domains fused onto constant domains or only the complementarity determining regions grafted onto appropriate framework regions in the variable domains.
In the description, reference is made to a number of publications by number. The publications are listed in numerical order at the end of the description.
Natural immunoglobulins have been known for many years, as have the various fragments thereof, such as the Fab, (Fab').sub.2 and Fc fragments, which can be derived by enzymatic cleavage. Natural immunoglobulins comprise a generally Y-shaped molecule having an antigen-binding site at the end of each arm. The remainder of the structure, and particularly the stem of the Y, mediates the effector functions associated with immunoglobulins.
Natural immunoglobulins have been used in diagnosis and, to a more limited extent, in therapy. However, such uses, especially in therapy, have been hindered by the polyclonal nature of natural immunoglobulins. A significant step towards the realisation of the potential of immunoglobulins as therapeutic agents was the discovery of monoclonal antibodies (1) of defined antigen specificity. Most MAbs are produced by fusions of rodent spleen cells with rodent myeloma cells. They are therefore essentially rodent MAbs. There are very few reports of the production of human MAbs.
There have been made proposals for making non-human MAbs less antigenic in humans. Such techniques can be generically termed "humanizing" MAbs. These techniques generally involve the use of recombinant DNA technology to manipulate DNA sequences encoding the polypeptide chains of the antibody molecule.
Some early methods for carrying out such a procedure are described in EP-A-0 71 496 (Res. Dev. Corp. Japan , EP-A-0 173 494 (Stanford University), EP-A-0 194 276 (Celltech Limited) and WO-A-8 702 671 (Int. Gen. Eng. Inc.).
In an alternative approach, described in EP-A-87302620.7 (Winter), the complementarity determining regions (CDRs) of a mouse MAb have been grafted onto the framework regions of the variable domains of a human immunoglobulin by site directed mutagenesis using long oligonucleotides.
It has been widely suggested that immunoglobulins, and in particular MAbs, could potentially be very useful in the diagnosis and treatment of cancer (2,3). There has therefore been much activity in trying to produce immunoglobulins or MAbs directed against tumour-specific antigens. So far, over one hundred MAbs directed against a variety of human carcinomas have been used in various aspects of tumour diagnosis or treatment (4).
In our copending application Ser. No. 353,632 (ref; PA 149), also claiming priority from British patent application No. 8720833, there is described a humanised antibody molecule (HAM) having an antigen binding site wherein at least the complementarity determining regions (CDRs) of the variable domain are derived from the mouse monoclonal antibody B72.3 (B72.3 MAb) and the remaining immunoglobulin-derived parts of the HAM are derived from a human immunoglobulin. The B72.3 MAb is a mouse MAb of the type IgG1 raised against a membrane-enriched extract of a human liver metastatis of a breast carcinoma (5). The B7
REFERENCES:
patent: 4751077 (1988-06-01), Bell et al.
Lyons et al, "Site-specific attachment to recombinant antibodies via introduced surface cysteine residues", Protein Engineering vol. 3, No. 8, 1990, pp. 703-708.
Kabat, "Investigation and Exploitation of Antibody Combining Sites", Plenum Press, 1985, pp. 3-22.
Davies et al, "Investigation and Exploitation of Antibody Combining Sites", Plenum Press, 1985, pp. 51-60.
Novotny et al, "Antigenic determinants in proteins coincide with regions accessible to large probes (antibody domains)", Proc. Natl. Acad. Sci. vol. 83, Jan. 1986, pp. 226-230.
Connolly, "Solvent-Accessible Surfaces of Proteins and Nucleic Acids", Science, Aug. 1983, vol. 221, pp. 709-713.
Adair John R.
Bodmer Mark W.
Lyons Alan H.
Owens Raymond J.
Whittle Nigel R.
Budens Robert D.
Celltech Limited
Lacey David L.
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