Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated to proteinaceous toxin or fragment thereof
Reexamination Certificate
2000-02-07
2003-11-11
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated to proteinaceous toxin or fragment thereof
C424S130100, C424S133100, C424S135100, C424S141100, C424S143100, C424S144100, C424S153100, C424S154100, C424S173100, C424S178100, C424S179100, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750, C530S391100, C530S391700
Reexamination Certificate
active
06645494
ABSTRACT:
This application is a Rule 371 Application of PCT Application No. PCT/NL98/00357 (Publication No. WO 9858678), filed on Jun. 22, 1998 which claims priority to EP 97201895.6, filed on Jun. 20, 1997.
FIELD OF THE INVENTION
This invention relates to methods of treating diseases of in which the immune system is involved. In particular, this invention relates to methods of treating T-cell mediated autoimmune diseases such as multiple sclerosis and various malignancies of lymphoid origin.
BACKGROUND OF THE INVENTION
Immunotoxins:
Immunotoxins are chimeric molecules in which cell-binding ligands are coupled to toxins or their subunits. The ligand portion of the immunotoxin is usually a monoclonal antibody (Mab) that binds to selected target cells. The toxin portion of the immunotoxin can be derived form various sources. Most commonly, toxins are derived from plants or bacteria, but toxins of human origin or synthetic toxins (drugs) have been used as well. Toxins used for immunotoxins derived from plants or bacteria all inhibit protein synthesis of eukaryotic cells. The most widely used plant toxin ricin, consist of two disulfate-linked polypeptides A and B (Olsnes et al., in
Molecular Action of Toxins and Viruses
p51-105 (1982)). The most widely used bacterial toxin is Pseudomonas exotoxin (PE). Pseudomonas exotoxin is produced by the bacterium as a single-chain protein (Allured et al.,
Proc. Natl. Acad. Sci. USA
83:1320 (1986)). Another group of plant-derived toxins used in ITs are single-chain proteins (type I RIP), frequently found in plants and have similar enzymatic properties as the A-chain of ricin (reviewed in Stirpe and Barbieri
FEBS Lett
. 195:1 (1986)), these type I RIP however lack the B-chain. The absence of binding activity and as a consequence the inability of the native toxin to bind to cells significantly decreases the non-specific toxicity and makes these toxins extremely interesting for usage in ITs. To target these toxins to potential harmful cells, they are coupled to a Mab against a specific protein on the surface of these targeted cells. The cross-linker used to join the Mab and the toxin must remain stable extracellular, but after internalization of the conjugate into the cell, be labile intracellular so that the toxin fragment can be released in the cytosol and target to the appropriate intracellular location. A complete Mab consists of two heavy and two light chains and can be chemically coupled to the toxin. Using this chemical coupling usually several toxin molecules are coupled to one Mab molecules, resulting in protein complexes of considerable size. An alternative to complete Mabs, is to use single-chain antibody fragments (scFv), which consist of only the variable part of the heavy chain (VH) and the variable part of the light chain (VL) coupled via a short linker (Pastan et al.,
Annu. Rev. Biochem
. 61:331 (1992)). The usage of scFv-ITs has a number of advantages compared to chemically coupled ITs. First, the scFv can be cloned via a short linker to a toxin and can be expressed as fusion-protein in a bacterial expression system. Secondly, tissue penetration is a major obstacle when chemical coupled IT-conjugates were used in various animal models, the scFv format being superior in this respect. The use of a scFv as ligand portion of an immunotoxin reduces the size of ligand portion with a factor 6 as compared to a complete Mab and in these recombinant molecules one toxin molecule is linked to one scFv reducing the size even further. Since a scFv-IT is produced as one molecule unwanted cleavage of the toxin and the ligand in the circulation can not occur. The capability of scFv-ITs to specifically eliminate cells, revealed that intracellular cleavage of the ligand and toxin part, that is necessary when ITs are used, is not necessary for the cytotoxic effect of certain scFv-ITs.
Various types of immunotoxins directed against different cellular targets have been evaluated in vivo, both in animal models and in phase I or II clinical trials. The vast majority of clinical studies with immunotoxins has been performed for anti-tumor therapy using ricin A chain or blocked ricin (Frankel et al.,
Leukemia and Lymphoma
26:28 (1997), Lynch et al.,
J. Clin. Onc
. 15:723 (1997)). Reports on the administration of immunotoxins containing type I RIPs are limited. Thusfar only two studies have been published, the first using saporin-S6 coupled to an anti-CD30 Mab (Falini et al.,
Lancet
339:1195 (1992)) and the second using the PAP toxin coupled to an anti-CD19 Mab (Uckun et al.,
Blood
79:3369 (1992)). An increasing number of preclinical studies using immunotoxins containing various different type I RIPs (momordin, gelonin, saporin, bryodin and bouganin) are currently under development.
The CD40L Molecule:
The CD40L molecule belongs to the TNF/CD40L gene family (Armitage et al.,
Curr. Opin. Immunol
. 6:407 (1994)). Although TNF is a soluble cytokine, it is initially synthesized as a membrane associated molecule. Most of the members of the of the TNF/CD40L receptor family are type II transmembrane proteins. Initially it was reported that the expression of the CD40L was restricted to activated CD4
+
T cells. Now it has also been detected on B cells from autoimmuine patients, on mast cells and on baophils. The cell surface expression of CD40L is tightly regulated, specific signals are needed for its appearance and, once engaged with CD40 the molecule rapidly disappears again.
Autoimmune Diseases:
A normal functioning immune system has self-regulating mechanisms to terminate the immune response when it is no longer needed. When these self-regulatory mechanisms become compromised, a person may develop a so-called autoimmune disease. Examples of autoimmune diseases are rheumatoid arthritis, multiple sclerosis, type I diabetes, lupus, thyroiditis, systemic lupus erythematosus and myasthenia gravis.
Multiple sclerosis (MS) is a severely disabling progressive neurological disease, involving autoimmune attack against myelin in the central nervous system. MS affects 1 in 1000 in the USA and Europe. Due to improved diagnosis that number is currently increasing. Onset of disease is usually around 30 years of age and, on average, patients are in need of treatment for another 28 years. Diagnosis of exacerbations and early identification of onset of exacerbations has improved greatly, allowing design of novel treatment strategies. Recently, the involvement of the CD40L molecule in the pathophysiology of MS has been demonstrated using the experimental allergic encephalomyelitis model in mice (Gerritse et al.,
Proc. Natl. Acad. Sci. USA
93:2499 (1996)). In this model, injection of mice with a blocking monoclonal antibody (Mab) to CD40L at the time of disease induction, completely prevents disease. Furthermore, in situ analysis of CD40L and CD40 in human MS brain has revealed that CD40 expression is abundantly expressed on macrophages in perivascular infiltrates. Frequencies of CD40L positive cells in these infiltrates were modest, but could be found in juxtaposition to CD40 positive cells, indicative of an ongoing cellular interaction.
Systemic lupus erythematosus (SLE) is an other autoimmune disease in which the CD40L molecule has been implicated. SLE, in contrast to most autoimmune diseases, has the potential to involve multiple organs. The clinical manifestations of SLE are extremely variable and diverse. Some patients only have mild involvement of skin and joints, require little medication and show spontaneous remissions. Whereas other patients suffer from severe and progressive glomerulonephritis that in the end does not even respond to high doses steroids and cyclophosphamide. SLE can manifest at nearly any age, but the disease onset is usually between 15 and 50 years. SLE affects about 8 times more females than males. The chance that a caucasian women in her life time develops SLE is about 1 in 700, whereas this incidence can be two to four times higher in hispanics or blacks. The overall prevalence of SLE is in the order 1 in 2000. SLE is characterized by a
Boer De Mark
Hartog Den Marcel Theodorus
Gambel Phillip
Handal & Morofsky
Tanox Pharma B.V.
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