Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds expression product or fragment thereof of...
Reissue Patent
2001-11-29
2003-02-25
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds expression product or fragment thereof of...
C424S178100, C424S179100, C424S180100, C424S181100, C424S141100, C424S001110
Reissue Patent
active
RE038008
ABSTRACT:
1. Technical Field
The present invention generally relates to methods for enhancing targeting of antibodies, antibody fragments, peptide hormones and steroid hormones, and conjugates thereof. More specifically, methods are disclosed employing blocking antibodies, fragments, hormones and other targeting agents, and conjugates thereof to reduce cross-reactive and nonspecific binding of specific antibodies, hormones and other targeting agents to non-target cells.
2. Background Art
Antibodies are proteins that have a binding site that is specific for a particular determinant, e.g., antigen or epitope, and other portions that bind to normal tissues in a nonspecific fashion. There are several immunological concepts, all related to antibody binding, that require definition.
Target-specific binding: Binding of the antibody, whole or fragment, hormones, other targeting agents or conjugate thereof, through the antibody's binding site, to the epitope recognized by said antibody on cells expressing said epitope's or hormone's receptor, where said cells are the desired target of the antibody, whole or fragment, or hormone, other targeting agent, or conjugates thereof.
An example of target-specific binding is binding of the antibody, whole or fragment, or conjugate thereof, to tumor cells where the antibody in question can also bind specifically to normal cells. The component of binding to the tumor cells is target-specific. Another example is binding of bombesin, or gastrin-releasing peptide, to small cell lung carcinoma.
Cross-reactive binding: Binding of the antibody, whole or fragment or hormone, other targeting agent or conjugate thereof, through the antibody's binding site, to the epitope recognized by said antibody on cells expressing said epitope or hormone receptor, where said cells are not the desired target of the antibody, whole or fragment, or hormone or conjugate thereof.
An example of cross-specific binding is binding of the antibody, whole or fragment, or conjugate thereof, to normal lung by antibody binding site to the same or structurally homologous epitope as is present on a tumor cell. The component of binding to the normal lung cells by the antigen-binding site of the antibody is cross-reactive. Another example is the binding of bombesin, or gastrin-releasing peptide, to normal cells in the stomach or pancreas.
Nonspecific binding: Binding of an antibody, whole or fragment, or hormone or conjugate thereof, through some mechanism other than the antigen-recognition binding site of the antibody or hormone, to cells other than the target cells.
An example of nonspecific binding is the uptake of antibody into the liver and spleen due to binding of the antibody by its Fc receptors onto cells in these organs.
A second example would be binding of mannose present in the ricin of antibody-ricin conjugate to mannose receptors on liver cells.
Specific antibody: Antibody that binds to epitope on desired target cells through its antigen-recognition sites. Specific antibodies may also bind to epitope or structural homolog present on non-target cells.
Irrelevant antibody: Antibody that does not bind to target cells by means of its antigen-recognition sites, but may bind to non-target and target cells through non-specific mechanisms, e.g., Fc portion of antibody binding to Fc receptors on cells in reticuloendothelial system (RES).
Blocking antibody: Antibody that inhibits the non-specific binding of pharmaceutically active specific antibody. Blocking antibodies may include irrelevant antibody or pharmaceutically inactive specific antibody or fragments or combinations thereof. The latter may also be called “cold-specific” antibody.
Pharmaceutically active antibody: Antibody that is diagnostically or therapeutically effective.
The use of antibodies are carriers for radionuclides and cytotoxins has been a goal of cancer of diagnosis and treatment since Pressman et al. showed that 131
I
labeled rabbit anti-rat kidney antibodies localized in the kidney after intravenous injection (Pressman, D., Keighly, G. (1948) J. Immunol. 59:141-46). Just a few years later, Vial and Callahan reported a dramatic, complete response in a patient with widely metastatic malignant melamoma treated with
131
I-antibodies raised against his own tumor (Vial, A. B. and Callahan, W. (1956), Univ. Mich. Med. Bull. 20: 284-86). In the 1960s, Bale and co-workers demonstrated that labeled antibodies to fibrin, which is often deposited in rapidly growing tumors, could localize in rat, dog and human tumors (65% of 141 patients) (Bale, W. F., et al. (1960) Cancer Res. 20:1501-1504 (1960); McCradle, R. J., Harper, P. V., Spar, I. L., et al., (1966) J. Nucl. Med. 7:837-44; Spar, I. L., Bale, W. F., Manack, D., et al. (1969) Cancer 78:731-59; Bale, W. F., Centreras, M. A., Goody, E. D. (1980) Cancer Res. 40:3965-2972). Several years later, Chao et al. demonstrated selective uptake of antibody fragments in tumors (Chao, H. F., Peiper, S. C., Philpott, G. W., et al. (1974) Res. Comm. in Chem. Path. & Pharm. 9:749-61).
Monoclonal antibodies (Kohler, G. and Milstein, C. (1975) Nature 256:495-97) offer advantages over the polyclonals used in these studies because of their improved specificity, purity and consistency among lots. These factors, plus their wide availability, have let to improved clinical applications of antibodies and their conjugates.
Even with monoclonals, however, most antibodies to human tumors have some normal tissue cross-reactivity. Compared to tumors, these cross-reactive sites may equally or preferentially bind injected antibody or conjugate and thus adsorb a substantial portion of the administered dose, especially if these sites are concentrated in well-perfused organs. If the antibody is conjugated to a toxin agent, there may be toxicity to the normal tissues that could be dose-limiting. Therefore, reducing normal tissue binding of the antibody or conjugates without adversely affecting their tumor localization would be advantageous.
Also needed in the art are methods to improve the targeting of immunoconjugates to tumor cells. Most immunoconjugates are produced by chemically linking an antibody to another agent. Another possibility is creating a fusion protein. The antibody itself, the process of linking, or the conjugated agent itself may cause decreased localization of the tumor due to nonspecific or cross-reactive binding.
Also needed in the art is a method to improve delivery of cytotoxins or biologic response modifiers (BRMs) to tumors using antibodies as carriers, while minimizing toxicity.
Also needed in the art are similar methods to improve delivery of cytotoxins or biologic response modifiers (BRMs) to tumors using hormones or other targeting agents as carriers, while minimizing toxicity.
Also needed in the art is a method to decrease formation of antiglobulins to injected antibody or immunoconjugates as there may be inhibition of binding or even toxicity when the same antibody is injected at a later time.
All of these issues can be addressed by the described methods that reduce cross-reactive and nonspecific binding of antibody and antibody conjugates, and are equally applicable to any substance that has a nonspecific uptake site or whose receptors are shared by non-target cells.
The methods of the present invention reduce cross-reaction and/or nonspecific binding of specific antibodies and hormones when administered to diagnose, stage, evaluate or treat diseases such as cancer in humans. The characteristic or specificity makes antibodies potentially useful agents for targeting defined populations of cells such as tumor cells that express tumor-specific (expressed uniquely by tumor cells) or tumor-associated (expressed by tumor cells and by a subpopulation of normal cells) antigens. The clinical utility of these specific antibodies, however, is compromised by the phenomenon of cross-reactive and nonspecific binding.
One method of markedly diminishing nonspecific uptake is to remove a nonspecific binding portion of the antibody, leaving the antigen binding portion [e.g.,
Abrams Paul G.
Morgan, Jr. Alton C.
Schroff Robert W.
Mertz Prema
NeoRx Corporation
Schwegman Lundberg Woessner & Kluth P.A.
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