Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells

Abstract

This invention discloses monoclonal antibodies (MAbs) which have little or no signaling activity as monomers become potent anti-tumor agents when they are converted into homoconjugates. The homoconjugates exert anti-growth activity by signaling G0 / G1 arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and does not require an Fc portion. These conjugates are potent, anti-tumor agents.

Description

[0001] The government owns rights in the present invention pursuant to grant number CA-28149 from the National Institutes of Health.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the fields of immunology and tumor therapy. More particularly, it concerns homoconjugates of antibodies which arrest cell growth and / or signal apoptosis in the tumor cells. The components of these homoconjugate antibodies can comprise a wide variety of antibodies but often and surprisingly do not require an Fc region to function and importantly activate fewer, or even no, undesired immunological reactions. [0004] 2. Description of Related Art [0005] During the past two decades, a variety of monoclonal antibodies (MAbs) have been selected for clinical use based on their effector functions and the most encouraging results have emerged from the treatment of NHL (Hjekman et al., 1991; Press et al., 1987; Meeker et al., 1985; Waldmann, 1992; Hale et...

AI Technical Summary

Benefits of technology

[0017] The present invention provides conjugates of monoclonal antibodies (MAbs) which can lack Fc regions and yet are as effective, or possibly more effective, at signaling cell cycle arrest and / or apoptosis of tumor cells than comparable MAb conjugates which contain Fc regions. Surprisingly, conjugates of the present invention can be comprised of MAbs which in their monomeric or unconjugated form have little or substantially no anti-tumor activity, indicating that the binding to and crosslinking of cell surface antigens to the conjugates elicits a negative signal. Conjugates of the present invention are relatively smaller and capable of better biodistribution and, because they cannot recognize Fc receptors and stimulate effector function, these novel conjugates do not elicit unwanted immune responses.

Problems solved by technology

It is postulated that either the target molecules could not readily mediate signals when bound to MAbs and / or that the ability of the MAbs to crosslink their target molecules was poor.

The therapeutic potential of MAbs has not been fully realized because there has been no paradigm for predicting which properties of the MAb are essential and how MAbs interact with other therapeutic modalities.

Unfortunately, these large concentrations of antibody can activate unwanted immune responses which clear the therapeutic antibodies from the system and reduce the efficacy of treatment.

Clearly, it is desirable to eliminate these unwanted immune responses in order to increase the efficacy of treatment, but to date, the means to eliminate these responses is not available.

The physical size of the molecule is also an important limiting factor.

Thus while hundreds of MAbs recognize tumor antigens, few MAbs have proven useful for the diagnosis and treatment of tumors and neoplastic diseases, because they are not specific enough, they fail to have sufficient affinity or avidity or are too large to reach their antigens.

Part of the difficulty in designing antibody conjugates which possess sufficient affinity and avidity for tumor antigens and are of an appropriate isotype or subclass to efficiently initiate cell cycle arrest or apoptosis is that few MAbs possess sufficient affinity and avidity to be useful.

IgM molecules have a higher valency but their size limits their ability to penetrate tissue and reach the desired antigenic target.

But these homoconjugates possess two or more Fc regions; and thus, they can still elicit undesired immune responses which reduce successful treatment of a tumor or neoplastic disease.

And although increasing their valency results in increased avidity, the physical sizes of the homoconjugates are also increased which may limit or even prevent them from being able to physically reach target epitopes.

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