Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof

Abstract

Methods for improved targeting of antibody, antibody fragments, peptides hormones, steroid hormones and conjugates thereof are disclosed. Enhanced delivery to target cells of antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, specific for a population of cells of a mammal comprises steps of administering to said mammal an adequate dosage of blocking antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, and administering to said mammal an effective dosage of said antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, specific for said population of cells. In the preferred embodiment, the specific antibodies are monoclonal antibodies directed toward tumor-associated antigen in man.

Description

1. Technical FieldThe 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 ArtAntibodies 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...

AI Technical Summary

Benefits of technology

The administration of the blocking antibodies is preferably done prior to the administration of the specific antibodies; alternatively, such blocking antibodies may be administered simultaneously with the specific antibody. The effective dosage of the antibodies or fragments thereof specific for a said population of cells is either diagnostically effective or therapeutically effective. The preferred mammal of the methods disclosed herein is man.

An additional preferred embodiment of the methods disclosed herein is for enhancement of the localization of antibodies or fragments thereof specific for a cross-reactive antigen contained within a mammal's tissue or organ. This method comprises the steps of directly perfusing said tissue or organ with an adequate dosage of blocking antibodies or fragments thereof and then administering systemically to the mammal an effective dosage of said antibodies or fragments thereof specific for said antigen contained within said tissue or organ that is also present or target cells.

A related aspect of the present invention discloses a method for reducing within a mammal the production of anti-immunoglobulin directed against antibodies or fragments thereof specific for a population of target cells. This method comprises the steps of administering to said mammal in adequate dosage of blocking antibodies or fragments thereof capable of stimulating the production of anti-immunoglobulin directed against said blocking antibodies or fragments thereof and administering to said mammal a therapeutically effective dosage of said antibodies or fragments thereof specific for said target cells, wherein said therapeutically effective dosage is smaller than said adequate dosage of blocking antibodies or fragments thereof.

Problems solved by technology

If the antibody is conjugated to a toxin agent, there may be toxicity to the normal tissues that could be dose-limiting.

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.

The clinical utility of these specific antibodies, however, is compromised by the phenomenon of cross-reactive and nonspecific binding.

This does not usually compensate for the decreased serum half-life of the fragments resulting in decreased tumor accumulation compared to whole antibody.

Generally, a major obstacle to the successful clinical use of antibodies and conjugates thereof has been inadequate delivery to target cells.

Studies with radiolabled antibodies have demonstrated that part of the problem causing low tumor accumulation is the localization of radiolabeled antibody in other organs, such as liver, spleen, marrow, lung or kidney.