Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1997-09-26
2000-03-07
Burke, Julie
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 697, 435 723, 435334, 435344, 4241331, 4241381, 4241441, 4241551, 5303873, 5303877, 53038822, 5303888, A61K 39395, C12N 1513, G01N 3353
Patent
active
060338768
DESCRIPTION:
BRIEF SUMMARY
The invention comprises high-affinity Hodgkin's disease cell specific anti-CD30 antibodies which prevent proteolytic cleavage and release of membrane-bound CD30 antigen, a method of production and the use of said antibodies.
INTRODUCTION
The CD30 activation marker was originally discovered as the Hodgkin-associated Ki-1 antigen (Schwab et al. (1982) (1)). CD30 is a membrane glycoprotein with a molecular weight of 120 kDa (Froese et al. (1987) (8)). A soluble form of the CD30 (sCD30) is released from cell membranes (Hansen et al. (1989) (2)) which is detectable in sera of Hodgkin patients (Josimovic-Alasevic et al. (1989) (3), Pfreundschuh et al. (1990) (4)) and the serum levels of the sCD30 correlate with the severity and the clinical stage of the disease (Pizzolo et al. (1990) (5)). sCD30 is a cleavage product of the cell surface-bound CD30 molecule, as it could be shown that the glycosylation pattern of CD30 and sCD30 is identical. CD30 is cleaved by a specific acting protease.
The membrane-associated CD30 antigen is regarded as a possible target for treatment of Hodgkin's-diseased patients with immunotoxins. However, the efficacy of the various antibody-toxin conjugates show rather big differences (Engert et al. (1990) (6)). Moreover, the CD30-specific monoclonal antibody (mAb) Ki-1 enhanced the release of the sCD30 from the Hodgkin-derived cell lines L428 and L540 as well as from the CD30+ non-Hodgkin's lymphoma cell line Karpas 299 (Hansen et al. (1991) (7)).
Shedding of CD30 molecules from the cell surface of tumour cells weakens or may even make obsolete the use of this antibody especially in the form of immunotoxins in the treatment of cancer, since such antibodies bind to CD30 as well as to sCD30.
The conjugate of antibody Ki-1 with the Ricin A-chain, for instance, was a rather ineffective immunotoxin and it was concluded that this ineffectiveness was due to the rather low affinity of antibody Ki-1 (Engert et al. (1990) (6)). Two other reasons may also account for the weak toxicity of Ki-1-Ricin A-chain conjugates: a) Antibody Ki-1 enhanced the release of the sCD30 from the Hodgkin-derived cell lines L428 and L540 as well as from the CD30+ non-Hodgkin's lymphoma cell line Karpas 299 Hansen et al. (1991) (7)); b) the relatively great distance of the Ki-1 epitope from the cell membrane is also not favorable for the construction of potent immunotoxins (Press et al. (1988) (11), May et al. (1990) (12)).
At the Fourth Workshop on Leukocyte Differentiation Antigens in Vienna in February 1989, monoclonal antibodies were submitted by three different laboratories and finally characterized as belonging to the CD30 group. Co-cultivation experiments by the inventors of L540 cells with various antibodies according to the state of the art, followed by the isolation of sCD30 from culture supernatant fluids, revealed that the release of the sCD30 was most strongly increased by antibody Ki-1, and weakly enhanced by the antibody HeFi-1, whilst being more strongly inhibited by the antibody Ber-H2. However, the antibody Ber-H2 also labels a subpopulation of plasma cells (R. Schwarting et al. (1989) (10)) and G. Pallesen (9) describes, on page 411, that Ber-H2 is cross-reacting with an epitope of an unrelated antigen which is altered by formaldehyde. Therefore, in the state of the art, no anti-CD30 antibody is known which does not release sCD30 and is specific for Hodgkin and Reed-Sternberg cells.
SUMMARY OF THE INVENTION
It was therefore the object of the invention to provide new CD30-specific antibodies which do not promote the release of the sCD30, but inhibit the formation of the sCD30 instead and thus would possibly allow the formation of powerful immunotoxins. In the present invention there is described the production and reactivity of new CD30-specific antibodies with special reference to the relative positions of the epitopes recognized by these and other established anti-CD30 antibodies on the extracellular part of the CD30 molecule. The new antibodies according to the invention exhibit a nearly complet
REFERENCES:
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Hansen Hinrich-Peter
Lemke Hilmar
Boehringer Mannheim GmbH
Burke Julie
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