Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Extracorporeal or ex vivo removal of antibodies or immune...
Reexamination Certificate
1993-10-12
2001-06-26
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Extracorporeal or ex vivo removal of antibodies or immune...
C604S004010, C604S005010, C604S028000
Reexamination Certificate
active
06251394
ABSTRACT:
DESCRIPTION
The present invention relates to a method and a system for reducing non-target levels of specific molecules intended for diagnostic and/or therapeutic applications to vertebrate hosts. In particular, it relates to methods, compositions and means for the extracorporeal removal from the blood circulation of exogenous targeting molecules pre-labelled with a specific affinity ligand which can bind with high affinity to a corresponding receptor immobilized to an extracorporeal device.
The invention is applicable in the removal of any type of exogenous targeting molecule from the blood circulation, provided that these agents are targeted to a specific type of tissue, a specific type of cell or a specific type of extracellular or intracellular marker, and provided that this targeting molecule can be labelled with an affinity ligand without severely affecting the intrinsic affinity and specificity of the targeting molecule. A second requirement is the availability of a receptor to which the affinity ligand has a high affinity, and which in its immobilized form could be used to eliminate the targeting molecule from the blood circulation without affecting endogenous blood components or other exogenous administered components.
Antibodies have been found useful as targeting vehicles for diagnostic and therapeutic agents, inter alia radioisotopes, magnetic resonance imaging agents, enzymes, toxins and cytotoxic drugs or prodrugs. These have been used especially in diagnosis or treatment of cancer. Commonly, antibodies conjugated to diagnostic or therapeutic agents have been administered systemically, but other modes of administration have also been used.
In general, present immunotherapeutic strategies involve the administration of exogenous (non-human) antibodies to the patient These antibodies art intended to interact only with a specific subset of cells while leaving the other cells unaffected. The antibodies are usually conjugated to a lethal agent such as cytotoxic drugs or radioactive isotopes. In these cases, the therapeutic principle will be based entirely on the effect of the exogenously added therapeutic agent. Antibodies can also alone trigger a cytotoxic effect on cells exposing antigens to which the antibodies bind specifically. This is likely to be caused by two different but immunologically related mechanisms. One of these mechanisms, the antibody-dependent cell-mediated cytotoxicity (ADCC), acts through activation of cytotoxic lymphocytes. In the second case, cell lysis is dependent on complement activation which is triggered by antibodies bound to the specific cells. The conceptual simplicity of localizing tumours with radiolabelled antibodies in conjunction with external imaging has led to a great deal of research activity over the past years. Although techniques have improved, the clinical results are still hampered by some major limitations. Several of these limitations are due to parameters which are patient-dependent and can clearly not be altered.
The most important single determinant of detection sensitivity is, nevertheless, the uptake ratio of the localizing antibody on the tumour compared with the same antibody on surrounding normal tissues. Consequently, most work has centered on attempts to improve this uptake ratio with, as yet, limited success. Earlier work in this field has been based on polyclonal antibodies. The development of monoclonal antibodies would seem to have created ideal probes for these attempts. Monoclonal antibodies can be raised to tumour-selective antigens and because of the extremely high specificity there would be very little cross-reactivity with other cell markers, and consequently no, or very little, interaction with cells lacking these markets. However, human studies using mostly mouse monoclonal antibodies have, by and large, been disappointing in that respect. The extreme specificity of monoclonal antibodies, particularly if these antibodies recognize only one epitope per antigen might in some cases lead to a disadvantage in so far that a too small quantity of antibodies will be bound to the target cells, particularly if the number of accessible antigens is small. Mouse monoclonal antibodies might also, in spite of their intrinsic specificity, produce falsely positive localization due to their interaction with human Fc receptors on non-target cells. To overcome these problems, attempts have been made to use immunological fragments derived from monoclonal antibodies. Apart from the fact that these fragments most often lack the ability to interact with cells by non-idiotypic binding, they should also gain access to the target cells more readily than the intact molecule. Smaller molecules like Fab and F(ab)
2
fragments do indeed penetrate more rapidly into the tumour (Matzku et al., Int. J. Cancer Suppl. 2, 1988. 11). However, the driving force causing a favourable diffusion of labelled antibodies into tumours is mainly dependent on the concentration gradient (Weinstein et al., Ann. N.Y. Acad. Sci., 1988, 199). Consequently, the blood concentration over time might be more important than the molecular size. Although the uptake of antibody fragment into the tumour might be higher, there is also likely to be a faster secretion of the antibody moieties into the urine. This is supported by data showing that the tumour concentration of antibodies was higher using intact antibody than using the corresponding antibody fragments (Wilbanks et al., Cancer 48, 1981, 1768).
Another approach has been the subtraction of background activity by simultaneous injection of non-target specific antibodies, carrying a second isotope. The latter should mimic the non-specific distribution of the tumour-directed antibody but emits a different photon energy. The two images are then subtracted. Although, this technique should in theory improve the contrast, there are, however, several practical problems. According to Bradwell et al. (Immunology Today 6, 1985, 163) artifacts may result from differences in energy between the two isotopes leading to positioning variability and different tissue attenuation of the gamma rays. Secondly, if the in vivo characteristics of the two isotopes are dissimilar, there will be a differential organ accumulation of the two detached isotopes. For example, the bladder always contains an excess of free iodine or technetium which leads to hot or cold areas. Inequalities may also occur around the heart or stomach. Thirdly, the process of subtraction, while improving contrast, introduces additional statistic fluctuations without increasing the signal. A further disadvantage of this method is that the enhancement of contrast is achieved at the expense of introducing additional radioactive material into the body.
Methods have also been described to enhance the clearance of residual circulating antibodies from the blood circulation. It has been suggested that this could be achieved either by the administration of a second antibody or by modification of the carbohydrate part of the antibody or the antibody conjugate to enhance clearance by hepatic cells. In the former approach, a second antibody which specifically binds to the primary imaging antibody is administered. The second antibody is injected into the patient after sufficient time has elapsed following injection of the primary antibody. The time difference should permit maximum selective uptake of the primary antibody in the tumour to be imaged or treated therapeutically. The second antibodies will form aggregates with unbound imaging antibodies and these aggregates will then be cleared from the blood circulation of the patient through the body's own reticuloendothelial system. There are, however, conflicting views among experts in the field whether this is a feasible method or not (A. Klausner, Biotechnology, 5, 1987,533). Such a method would for example mask several vital organs like spleen, lung, kidney and liver, since these are the organs mainly responsible for the uptake and clearance of the artificially induced immune complexes, referred to as aggregates. It s
Lindgren Lars
Nilsson Rune
Norrgren Kristina
Sandberg Bengt
Sjögren Hans Olof
Mitra Medical Technology AB
Swanson & Bratschun L
Witz Jean C.
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