Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
2000-06-23
2002-06-04
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C424S001110, C424S001490, C424S085200, C424S130100, C424S144100, C424S184100, C530S387100, C530S387300, C530S388220
Reexamination Certificate
active
06399068
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a fusion protein of a component of an internalizing receptor system and a moiety that binds to a specific cellular surface marker on a cell, to a conjugate of a toxin and a ligand for the internalizing receptor system, and to a method of tumor therapy using the conjugate and internalizing receptor system.
There is now a fairly large and growing body of experience in the use of monoclonal antibodies (mAbs) for the therapy of lymphoma. Several studies targeting different B-cell restricted CD (clusters of differentiation) antigens have shown promising results. These studies have used radiolabeled mAbs and, to a lesser extent, mAb-toxin conjugates, and have targeted CDs19-22, CD37, and HLA-DR.
MAbs used in lymphoma therapy differ in their ability to bind cognate antigen and to become internalized. For example, CD22 exhibits efficient internalization as well as reexpression of antigen after internalization. It suffers, however, from relatively low expression levels on most B-cell malignancies, and is not widely expressed, e.g., it is expressed on only 30-50% of cases of B-cell lymphocytic leukemia (B-CLL).
The present inventor has studied an anti-CD22 mAb, LL2. Preliminary studies using LL2 labeled with
131
I for both therapy and imaging of NHL have produced response rates of 30-90+%, with varying percentages of complete responses and differences in durability of response. Higher response rates and longer disease-free survival have been associated with higher total doses of antibody and of radioactivity, which usually have required autologous bone marrow or peripheral stem cell rescue. While the results are encouraging, it is desired to increase therapeutic efficacy and decrease toxicity, particularly myelotoxicity.
The CD20 antigen, in contrast to the CD22 antigen, is a quite highly expressed B-cell restricted antigen that is expressed on a wide range of B-cell malignancies, ranging from acute lymphocytic leukemia (ALL) to the more differentiated B-Cell (B-CLL) and non-Hodgkin's lymphoma (NHL), and even to hairy cell leukemia (HCL). It generally is expressed on cells in the vast majority of cases of these malignancies at a high antigen density. A major disadvantage of CD20 is that it is a slowly internalizing antigen. For RAIT directed against CD20 this feature may not be a problem, but it militates significantly against the use of CD20 for toxin-based therapy.
A further problem of CD20 is the fact that B-cell malignancies exhibit a more rapid dissociation of bound anti-CD20 mAbs from the surface as compared to nonlymphoma tumor cells. This suggests that a therapy that uses bonding to a B-cell restricted antigen, particularly those characterized by slow internalization, would not be successful.
A variety of mAb-toxin constructs have been tested in both in vitro experiments and human trials. These studies have demonstrated potent and specific effects of these reagents. Most of the toxin molecules that have been used derive from either plant or bacterial sources and hence produce allergenic sensitization in patients. This severely limits the duration of therapy.
While major progress has been made in the therapy of B-cell malignancies such as NHL and B-CLL, there remain a substantial number of patients with B-cell malignancies who exhibit primary resistance to, or relapse after, optimal chemotherapy. A therapy that is effective over long periods of time in most or all patients with B-cell malignancies is desired.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a more effective and less toxic anti-tumor therapy, particularly a therapy for treatment of B-cell malignancies, such as NHL and B-CLL.
It is another object of the invention to improve the value as antigenic targets of slowly internalizing surface antigens such as the CD20 antigen.
It is a further object of the invention to overcome the tendency of antibodies bound to the surface of lymphoma cells to dissociate rapidly from the surface of the cells.
It is yet another object of the present invention to use B-cell restricted antigens, particularly the CD20 antigen, in anti-tumor therapy.
These and other objects of the invention are achieved by providing a conjugate of toxin or therapeutic radionuclide and IL-15, and a fusion protein comprising a bispecific antibody that has a first specificity for a cell marker specific to a malignant cell and a second specificity for a region of IL-15&agr;, each optionally further comprising a diagnostic radionuclide, which are useful therapeutic reagents for treating leukemias and lymphomas.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has been discovered, surprisingly, that the value of surface antigens as antigenic targets can be improved significantly by functionally linking them to a high affinity, internalizing receptor system. The present invention is of particular advantage in the case of surface antigens that do not internalize or that internalize slowly. A preferred example of a high affinity, internalizing receptor system is the IL-15 receptor system. When the IL-15 receptor system is used, it can be employed with all malignant cells that contain the &bgr;/&ggr;
c
chains of IL-15 receptor. The presence of &bgr;/&ggr;
c
chains of IL-15 on the cells provides the basis for a continuously internalizing receptor system that can be bridged to a surface antigen, particularly a slowly internalizing antigen, by way of a bispecific fusion protein and cognate ligand. The method according to the invention results in increased intracellular delivery into the malignant cell of cytotoxic ligands. It also improves methodologies in which a radionuclide is used as a therapeutic agent, by producing a tighter binding of the radionuclide to the malignant cell and by reducing dissociation of the targeting agent from the cell surface.
In accordance with the invention, malignant cells are pretargeted with a fusion protein. The fusion protein comprises a region of IL-15&agr;, preferably an extracellular domain, and a bispecific antibody or antibody fragment that has a first specificity for a cell marker specific to a malignant cell marker and a second specificity for the region of IL-15&agr;. The fusion protein is positioned on the malignant cells by means of the surface antigen expressed by the malignant cells. In an alternative embodiment, the fusion protein is formed in situ, by first administering the bispecific antibody, and then administering IL-15&agr; which binds to the bispecific antibody that is already bound to the malignant cells. In either case, addition of an armed ligand comprising IL-15 ligand armed with a toxin or with a radionuclide then results in the formation of a trimeric complex of the &bgr;/&ggr;
c
chains of IL-15 receptor, in which the &agr;-chain of IL-15 receptor attached to the surface antigen and IL-15/toxin and/or radionuclide conjugate. Alternatively, both the fusion and the trimeric complex can be formed in situ. This leads to rapid internalization of toxin and/or radionuclide into the malignant cells. While internalization is not necessary for a therapeutic radionuclide to be effective, the trimeric complex provides a tighter binding to the malignant cells, and thus improves these modalities as well.
Receptor complexes for both IL-2 and IL-15 have three primary chains. The &bgr; and &ggr;
c
chains are common to the two receptors, and there are individual, private alpha chains, IL-2R&agr; and IL-15R&agr;. The IL-2/IL-2 receptor system consists of at least three subunits, IL-2R&agr;, IL-
Foley & Lardner
Immunomedics Inc.
Mertz Prema
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