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Novel sez6 modulators and methods of use

a technology of modulators and sez6, which is applied in the field of new compounds, can solve the problems of inability to meet the needs of treatment, certain cancers are non-responsive or minimally responsive to such treatments, and treatment, such as surgery, may not be viable alternatives, etc., to achieve the effect of reducing tumorigenic signaling, and reducing the frequency of tumor initiating cells

Inactive Publication Date: 2019-01-24
ABBVIE STEMCENTRX LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that SEZ6 immunogens are associated with tumor cells that contribute to the development of various cancers. The invention provides a method for reducing tumorigenic signaling by tumor initiating cells, which can lead to more effective treatment of SEZ6-related disorders. The method can be used in both in vivo and in vitro settings and can help diagnose cancer and track the progress of treatment. The technical effects of this invention include the development of therapies for cancer stem cells and the improved ability to diagnose and treat cancer.

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.
Unfortunately, certain cancers are non-responsive or minimally responsive to such treatments.
For example, in some patients tumors exhibit gene mutations that render them non-responsive despite the general effectiveness of selected therapies.
Moreover, depending on the type of cancer and what form it takes 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 treat 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 relatively 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 for proliferative disorders.

Method used

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  • Novel sez6 modulators and methods of use
  • Novel sez6 modulators and methods of use
  • Novel sez6 modulators and methods of use

Examples

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Effect test

example 1

Identification of Tumors Having Neuroendocrine Features and Analysis of Marker Expression Using Whole Transcriptome Sequencing

[0654]Neuroendocrine tumors (NETs) arising from the dispersed endocrine system are rare, with an incidence of 2-5 per 100,000 people, but highly aggressive. Neuroendocrine tumors occur in the adrenal gland, kidney, genitourinary tract (bladder, prostate, ovary, cervix, and endometrium), pancreas, gastrointestinal tract (stomach and colon), thyroid (medullary thyroid cancer), and lung (small cell lung carcinoma, large cell neuroendocrine carcinoma, and carcinoid). These tumors may secrete several hormones including serotonin and / or chromogranin A that can cause debilitating symptoms known as carcinoid syndrome. These tumors can be denoted by positive immunohistochemical markers such as neuron-specific enolase (NSE, also known as gamma enolase, gene symbol=ENO2), CD56 / NCAM1, and synaptophysin. Traditional chemotherapies have not been successful in treating NETs...

example 2

Microarray and RT-PCR Analysis of Gene Expression in Selected NTX Tumors with Neuroendocrine Features

[0663]In an effort to identify additional NETs in the aforementioned NTX bank beyond those for which SOLiD whole transcriptome data existed, a larger set of NTX lines was examined using microarray analysis. Specifically, 2-6 μg of total RNA samples derived from whole tumors in 46 NTX lines or from 2 normal tissues were analyzed using a OneArray® microarray platform (Phalanx Biotech Group), which contains 29,187 probes designed against 19,380 genes in the human genome. More specifically, RNA samples were obtained (as described in Example 1) from forty-six patient derived whole NTX tumors comprising colorectal (CR), melanoma (SK), kidney (KD), lung (LU), ovarian (OV), endometrial (EM), breast (BR), liver (LIV), or pancreatic (PA) cancers. Normal colorectal (NormCR) and normal pancreas (NormPA) tissues were used as controls. Still more specifically, lung tumors were further subclassifie...

example 3

Expression of SEZ6 mRNA in Tumors having Neuroendocrine and Neural Features

[0670]Various techniques were used to identify tumors exhibiting neuroendocrine features including whole transcriptome sequencing (Example 1) and microarray and qRT-PCR (Example 2). The data thus generated was further analyzed in order to find potential therapeutic targets that are highly expressed in neuroendocrine tumors when compared to non-neuroendocrine tumors and normal tissues. As discussed in Example 1 it was found that SEZ6, a single pass transmembrane protein that is mainly expressed in the normal brain, has high expression in many neuroendocrine tumors (FIG. 6B).

[0671]The microarray data generated in Example 2 showed that tumors located in clusters C, D and E expressed neuroendocrine markers (FIG. 7B) and neural markers (FIG. 7E). The tumors in those same clusters also showed high levels of SEZ6 transcript, suggesting that SEZ6 is associated with tumors having neuroendocrine and neural features (FI...

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PUM

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Abstract

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

Description

CROSS REFERENCED APPLICATIONS[0001]This application claims priority from U.S. Provisional Patent Application Ser. No. 61 / 871,289 filed on Aug. 28, 2013, which is incorporated herein by reference in its entirety.SEQUENCE LISTING[0002]The instant application contains a sequence listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 27, 2014, is named “S69697 1130WO SEQL 082714 for filing” and is 462,073 bytes in size.FIELD OF THE INVENTION[0003]This application generally relates to novel compounds, compositions and methods of their use in diagnosing, preventing, treating or ameliorating proliferative disorders and any expansion, recurrence, relapse or metastasis thereof. In a broad aspect, the present invention relates to the use of seizure related 6 homolog (SEZ6) modulators, including anti-SEZ6 antibodies and fusion constructs, for the treatment, diagnosis or prophylaxis of neoplastic dis...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/68C07K16/18C07K16/28G01N33/574A61K39/00
CPCA61K47/6849C07K16/28A61K47/6803A61K2039/505C07K2317/77C07K2317/73C07K2317/34C07K2317/33C07K2317/24C07K2317/565C07K16/18C07K2317/20G01N33/57423G01N33/57407A61K47/6843A61P35/00A61P43/00A61P5/14
Inventor LIU, DAVIDROKKAM, DEEPTIBHEDDAH, SHEILALOPEZ-MOLINA, JAVIERSAUNDERS, LAURA
Owner ABBVIE STEMCENTRX LLC
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