Novel modulators and methods of use

Abstract

Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat hyperproliferative disorders are provided.

Description

CROSS REFERENCED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 421,157 filed Dec. 8, 2010 and Patent Cooperation Treaty (PCT); No. PCT / US2011 / 050451, filed Sep. 2, 2011, each of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This application generally relates to novel compositions and methods of their use in preventing, treating or ameliorating hyperproliferative disorders and any expansion, recurrence, relapse or metastasis thereof. In a broad aspect, the present invention relates to the use of ephrin-A ligand (EFNA) modulators, including anti-EFNA antibodies and fusion constructs, for the treatment or prophylaxis of neoplastic disorders. Particularly preferred embodiments of the present invention provide for the use of such EFNA modulators directed to EFNA1 and EFNA3 for the immunotherapeutic treatment of malignancies comprising a reduction in tumor initiating cell frequency.BACKGROUND OF THE I...

AI Technical Summary

Benefits of technology

[0015]In this regard it will be appreciated that the present invention is based, at least in part, upon the discovery that EFNA polypeptides (i.e., EFNA1 and EFNA3 as discussed below) are associated with tumor perpetuating cells (i.e., cancer stem cells) that are involved in the etiology of various neoplasia. More specifically, the instant application unexpectedly demonstrates that the administration of various exemplary EFNA modulators can mediate, reduce, inhibit or eliminate tumorigenic signaling by tumor initiating cells (i.e., reduce the frequency of tumor initiating cells). This reduced signaling, whether by reduction, elimination, reprogramming or silencing of the tumor initiating cells or by modifying tumor cell morphology (e.g., induced differentiation, niche disruption), in turn allows for the more effective treatment of EFNA associated disorders by inhibiting tumorigenesis, tumor maintenance, expansion and / or metastasis and recurrence.

[0016]In other embodiments the disclosed modulators of EFNA1 or EFNA3 may promote, support or otherwise enhance EFNA mediated signaling that may limit or restrain tumor growth. In other embodiments the disclosed modulators may interfere, suppress or otherwise retard EFNA mediated signaling that may fuel tumor growth. Further, as will be discussed in more detail below, EFNA1 and EFNA3 polypeptides may be involved in generating adhesive and repulsive forces between cells through integrin and cytoskeleton rearrangements or cytostructural modifications. Intervention in such intercellular interactions, using the novel EFNA modulators described herein, may thereby ameliorate a disorder by more than one mechanism (i.e., tumor initiating cell reduction and disruption of cellular adhesion) to provide additive or synergistic effects. Still other preferred embodiments may take advantage of the cellular internalization of ephrin-A ligands to deliver a modulator mediated anti-cancer agent. In this regard it will be appreciated that the present invention is not limited by any particular mechanism of action but rather encompasses the broad use of the disclosed modulators to treat EFNA associated disorders (including various neoplasia).

[0033]Such methods may be easily discerned in conjunction with the instant application and may be readily performed using generally available commercial technology such as automatic plate readers, dedicated reporter systems, etc. In selected embodiments the EFNA modulator will be associated with tumor perpetuating cells present in the sample. In other preferred embodiments the detecting or quantifying step will comprise a reduction of tumor initiating cell frequency and detection thereof. Moreover, limiting dilution analysis may be conducted as previously alluded to above and will preferably employ the use of Poisson distribution statistics to provide an accurate accounting as to the reduction of frequency.

Problems solved by technology

Unfortunately, disruption of cell proliferation and / or differentiation can result from a myriad of factors including, for example, the under- or overabundance of various signaling chemicals, the presence of altered microenvironments, genetic mutations or some combination thereof.

Sadly, far too many cancers are non-responsive or minimally responsive to such conventional treatments leaving few options for patients.

For example, in some patients certain cancers exhibit gene mutations that render them non-responsive despite the general effectiveness of selected therapies.

Moreover, depending on the type of cancer some available treatments, such as surgery, may not be viable alternatives.

Limitations inherent in current standard of care therapeutics are particularly evident when attempting to care for patients who have undergone previous treatments and have subsequently relapsed.

In such cases the failed therapeutic regimens and resulting patient deterioration may contribute to refractory tumors which often manifest themselves as a more aggressive disease that ultimately proves to be incurable.

Although there have been great improvements in the diagnosis and treatment of cancer over the years, overall survival rates for many solid tumors have remained largely unchanged due to the failure of existing therapies to prevent relapse, tumor recurrence and metastases.

Thus, it remains a challenge to develop more targeted and potent therapies.

Thus, the effectiveness of traditional, as well as more recent targeted treatment methods, has apparently been limited by the existence and / or emergence of resistant cancer cells that are capable of perpetuating the cancer even in face of these diverse treatment methods.

While progress has been made, inherent technical difficulties associated with handling primary and / or xenograft tumor tissue, along with a lack of experimental platforms to characterize CSC identity and differentiation potential, pose major challenges.

Images