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...
Reexamination Certificate
1999-01-15
2004-03-09
Helms, Larry R. (Department: 1642)
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...
C530S387100, C424S130100, C424S156100
Reexamination Certificate
active
06703488
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a conjugate, preferably a fusion protein, of a component of an internalizing receptor complex and a monoclonal antibody (mAb) that binds to a specific surface antigen on a cell, to a conjugate of a radionuclide or toxin and a ligand for the internalizing receptor system, and to a method of diagnosis or therapy using such genetic or chemical conjugates.
There is now a fairly large and growing body of experience in the use of mAbs for tumor therapy. Several studies targeting different antigens have shown promising results. These studies have used radiolabeled mAbs and, to a lesser extent, mAb-toxin conjugates.
MAbs used in tumor diagnosis and therapy differ in their ability to bind cognate antigen and to become internalized. For example, CD22 exhibits efficient internalization as well as reexpression of this antigen after internalization. It suffers, however, from relatively low expression levels on some B-cell malignancies, e.g., it is expressed on only 30-50% of cases of B-cell lymphocytic leukemia (B-CLL).
Other cell surface antigens such as HLA-DR and the CD20 antigen, in contrast to the CD22 antigen, are quite highly expressed B-cell antigens that are 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). These antigens are generally expressed on cells in the vast majority of cases of these malignancies at a high antigen density. A major disadvantage of these antigens is that they are slowly internalizing. This feature militates significantly against targeting HLA-DR and CD20 for toxin-based therapy.
A further problem with HLA-DR and CD20 is the fact that B-cell malignancies exhibit a more rapid dissociation of bound anti-HLA-DR and anti-CD20 mAbs from the surface as compared to nonlymphoma tumor cells. This suggests that a therapy that targets a B-cell restricted antigen, particularly those characterized by slow internalization, could be enhanced by addressing these issues.
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 neutralizing anti-toxin antibody responses in patients. This severely limits the duration of therapy.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide more effective methods of diagnosis and/or therapy for cancer and immunologically-mediated or infectious diseases.
It is another object of the invention to improve the value as antigenic targets of slowly internalizing surface antigens.
It is a further object of the invention to reduce the tendency of antibodies bound to the surface of tumor cells to dissociate from the surface of the cells.
These and other objects of the invention are achieved by providing a targeting moiety comprising a conjugate of an antibody linked to a ligand-binding region of a receptor subunit selected from the group consisting of IL-2R&agr;, IL-4R&agr;, IL-13R&agr; and IL-15R&agr;, which antibody is specific for a cellular antigen specific to a targeted cell. The targeting moiety may comprise a covalent conjugate in which the antibody is covalently linked to the ligand-binding region, a fusion protein of the antibody and the ligand-binding region, or a bispecific antibody that has a first specificity for a cellular antigen specific to a targeted cell and a second specificity for a rapidly internalizing receptor complex. In one embodiment, the antibody is specific to an antigen expressed by solid tumors, for example, CEA, and is linked to the ligand-binding region of IL-13R&agr;. In an alternative embodiment, the antibody is specific to HLA-DR and is linked to the ligand-binding region of IL-15R&agr;. A composition comprising a targeting moiety according to the invention and a pharmaceutically acceptable carrier also is provided.
A kit comprising a conjugate of IL-13 linked to a drug, radionuclide or toxin, and a targeting moiety comprising an antibody specific for a cell marker specific to a targeted cell, linked to the ligand-binding region of IL-13R&agr;, is provided. A second kit comprising a conjugate of IL-15 linked to a drug, radionuclide or toxin, and a targeting moiety comprising an antibody specific for a cell marker specific to a targeted cell, linked to the ligand-binding region of IL-15R&agr;, also is provided.
The invention provides a method of treatment for cancer, comprising first administering to a subject in need of such treatment a targeting moiety comprising an antibody specific for an antigen specific to a targeted cell, linked to the ligand-binding region of IL-13R&agr;, and then, after a predetermined time interval, administering to the subject a therapeutically effective amount of a conjugate of IL-13 linked to a drug, radionuclide or toxin. Another method of treatment for cancer or an immunologically-mediated or infectious disease comprises first administering to a subject in need of such treatment a targeting moiety comprising an antibody specific for an antigen specific to a targeted cell, linked to the ligand-binding region of IL-15R&agr;, and then administering to the subject a therapeutically effective amount of a conjugate of IL-15 linked to a drug, radionuclide or toxin.
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.
DESCRIPTION OF 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 useful cell surface antigens that internalize slowly.
The present invention is based on a fundamental property of cytokine and growth factor receptors, viz., their ability to rapidly and efficiently internalize. Examples of rapid internalization of receptor and ligand include intracellular transport of nutrients, as with the transferrin and low-density lipoprotein (LDL) receptors. Receptors for growth factors like insulin and epidermal growth factor (EGF) as well as cytokine receptors such as IL-1R, IL-2R and IL-4R also internalize rapidly. In all cases studied, except that of transferrin, the ligand undergoes proteolysis as a consequence of trafficking to the low pH, protease/acid hydrolase-containing lysosomal compartment. Molecules associated with the ligands, such as cholesterol bound to LDL or drugs, toxins, and radionuclides, linked to other ligands can exit to extra-lysosomal compartments where they can exert their effects.
The fate of a receptor following internalization varies depending on the receptor system. For example, it may recycle to the cell surface, as with the transferrin and LDL receptors, or it may itself be degraded. Lysosomal degradation of receptors has been reported for receptors such as the EGF receptor and contributes to receptor down-regulation and desensitization to subsequent ligand stimulation.
In some ligand/receptor systems, there is re-expression of receptors via de novo mRNA and protein synthesis. For example, CD22 is internalized rapidly after binding of the cognate LL2 mAb and is re-expressed as soon as 2 hours after a complete cycle of antigen saturation binding of cognate antigen by the specific mAb followed by internalization at 37° C. Further evidence of re-expression is found in the ability of a wide array of cytokine/growth factor-d
Burton Jack D.
Goldenberg David M.
Center for Molecular Medicine and Immunology
Foley & Lardner
Helms Larry R.
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