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Woomera Therapeutics, Inc.

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Patent
Woomera Therapeutics, Inc. | Date: 2016-10-10

Provided herein are pro-VP antagonists, such as antibodies and antigen-binding portions thereof specific for pro-VP, for identifying and targeting expressing cancer cells. Applicants additionally provide methods of using said compositions, for example to image cancer cells in vivo and in biological samples. The compositions may also be used for treating patients suffering from a provasopressin-expressing cancer. Provasopressin-expressing cancers include neuroendocrine cancer, pancreatic cancer, and prostate cancer.


Patent
Woomera Therapeutics, Inc. | Date: 2016-10-12

Provided herein are antagonists or binding agents of an abnormal vasopressin receptor V_(2 )(e.g., AbnV_(2)), such as antibodies and antigen-binding portions thereof specific for the receptor, for identifying and targeting cancer cells expressing such abnormal vasopressin receptor V_(2). Additionally provided are methods of using said antagonists or binding agents, for example, to image cancer cells or in biological samples, or diagnose cancers, both in vivo and in vitro. The antagonists or binding agents may also be used for treating patients suffering from a cancer expressing the abnormal vasopressin receptor V_(2), such as small cell lung cancer (SCLC), breast cancer, or ovarian cancer.


North W.G.,Woomera Therapeutics, Inc. | Pang R.H.L.,Woomera Therapeutics, Inc. | Cole B.F.,University of Vermont
Breast Cancer Research and Treatment | Year: 2011

A native form of mouse monoclonal IgG1 antibody called MAG-1, which recognizes an epitope on provasopressin, has been found to shrink and produce extensive necrosis of human breast tumor xenografts in nu/nu mice. We examined the ability of 90Yttrium-labeled and native MAG-1 to affect the growth in nu/nu mice of cancer xenografts that were estrogen-responsive (from MCF-7 cells) and triple-negative (from MDA-MB231 cells). The growth rates of treated cells were compared to those receiving saline vehicle and those receiving 90Yttrium-labeled and native forms of the ubiquitous antibody, MOPC21. Short-term treatments (4 doses over 6 days) not only with 90Yttrium-MAG-1 but also native MAG-1 produced large reductions in size of rapidly growing tumors of both types, while both 90Yttrium- MOPC21 and native MOPC21 had no effect. Native and 90Yttrium-MAG-1 effects were similar, and arrested tumors recommenced growing soon after treatments stopped. Increasing native MAG-1 treatment to single dosing for 16 consecutive days shrank tumors of both types with no regrowth apparent over a 20-day post-treatment period of observation. Pathological examination of such tumors revealed they had undergone very extensive (>66%) necrosis. © 2010 Springer Science+Business Media, LLC.


North W.G.,Dartmouth College | Gao G.,Dartmouth College | Memoli V.A.,Dartmouth College | Pang R.H.,Woomera Therapeutics, Inc. | Lynch L.,Dartmouth College
Breast Cancer Research and Treatment | Year: 2010

We demonstrate here that functional NMDAR1 and NMDAR2 receptors are expressed by Mcf-7 and SKBR3 breast cancer cell lines, and possibly by most or all high-grade breast tumors, and that these receptors are important for the growth of human breast cancer xenografts in mice. RT-PCR demonstrated mRNA for both NMDAR1 and NMDAR2 receptors are expressed in both Mcf-7 and SKBR3 cell lines, and these messages likely have sequences identical to those reported for human mRNAs. Proteins of the expected respective sizes 120 and 170 kD are generated from these mRNAs by the tumor cells. Cell growth was found to be significantly (P<0.0001) impaired down to 10% of normal growth by the irreversible NMDAR1 antagonists MK-801 and memantine with IC 50s ranging from 600 to>800 μM and from 200 to 300 μM for the two lines. Paradoxically, memantine with a lower binding affinity had the greater influence of the two inhibitors on cell viability. Immunohistochemical examination of highgrade invasive ductal and lobular breast cancer with our polyclonal antibodies against a peptide (-Met-Ser-Ile-Tyr-Ser-Asp-Lys-Ser-Ile-His-) in the extracellular domain of the NMDAR1 receptor gave specific positive staining for the receptor in all 10 cases examined. Positive staining was chiefly concentrated at the membranes of these tumor tissues. No staining with these antibodies was found for normal breast and kidney tissues. When Mcf-7 cells were grown as tumor xenografts in nu/nu mice, the growth of these tumors was completely arrested by daily treatments with MK-801 over 5 days. All of these data point to active NMDAR receptors being expressed by most breast cancers, and having an important influence on their survival. © Springer Science+Business Media, LLC. 2009.


North W.G.,Geisel Medical School at Dartmouth | North W.G.,Woomera Therapeutics, Inc. | Cole B.,University of Vermont | Akerman B.,Geisel Medical School at Dartmouth | Pang R.H.L.,Woomera Therapeutics, Inc.
Frontiers in Oncology | Year: 2014

Previously we demonstrated that human small-cell lung cancer (SCLC) seems to universally express the vasopressin gene, and this leads to the presence of a cell surface marker representing the entire pro-hormone precursor. In this study, we show this marker can be targeted with MAG-1, a mouse monoclonal antibody against a C-terminal moiety on pro-vasopressin. In vitro targeting of cell lines derived from primary and recurrent disease demonstrates attachment of antibody to the cell surface followed by internalization. In vivo targeting with 99Tc-labeled Fab fragments of MAG-1 shows selective attachment to xenografts. In vivo treatment of tumors from classical cell line, NCI H345, with either ~1.65 mCi (~1.65 mg)/kg body weight (BW) of 90Yttrium-labeled MAG-1, or ~1.65 mg/kg BW native MAG-1, delivered every second day for 6 days produced similar reductions in the growth rate to ~50% (p < 0.03). When dosing with native MAG-1 was escalated to daily amounts of ~3.3 mg/kg BW over 16 days, tumor growth rates fell to ~33% of saline controls (p < 0.005). Examination of tumors treated with this higher dosing demonstrated the presence in several of extensive apoptosis. Normal tissues seemed to be unaffected. A larger dosage of MAG-1 (~6.6 mg/kg BW) given daily for 14 days was used to treat xenografts of the variant cell line NCI H82 representing recurrent disease. This treatment decreased the rate of increase in tumor size by half, and doubling time ~3-fold. Increases in cleaved PARP supported increased apoptosis with antibody treatment. We believe these data provide evidence that the growth rate of SCLC tumors can be extensively reduced by treatment with MAG-1 antibody, and that a humanized form of this antibody could, in future, be potentially used for targeting therapy onto recurrent SCLC in patients. © 2014 North, Cole, Akerman and Pang.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 986.46K | Year: 2012

DESCRIPTION (provided by applicant): There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, Abner, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that an abnormal vasopressin type 2 receptor (AbnV2R) present on these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by Abner antibodies. The data from the studies of Phase 1 of the project clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse Abner significantly slows growth, but this growth is completely impaired when antibody treatment follows cyclophosphamide. Our data indicate AbnV2R expression is a feature common to all, or most, SCLC and that AbnV2R is a surface protein. Phase 2 is directed at advancing treatment of rSCLC with Abner by developing a human chimeric form (cAbner) of the mouse monoclonal antibody, and thena humanized form (hAbner) as potential clinical candidates. The ability of cAbner and hAbner to target and prevent growth of human variant SCLC xenografts in mice will then be tested. Phase 2 goals are directed towards (i) generating a chimeric form (cAbner) of mouse Abner with the constant regions of human IgG1; (ii) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by cAbner; (iii) modeling a humanized form (hAbner) of Abner from the cAbner with genetically grafting CDRs from the VH and VL regions of mMAG-1 into the DNA framework of a human antibody; (iv) establishing that the targeting, recognition, and treatment profiles of mAbner are retained by hAbner. These investigations will employ, RT-PCR, ligation, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, whole-body scintigraphy for 99mTechnetium, cytofluorographic and radiometric quantitation, confocal microscopy, radioligand binding, flow cytometry, and cell and tumor growth assessments with mechanism analysis in vitro and for nu/nu mice. A successful end-point of our Phase 2 studies would be the generation of cAbner and/orhAbner forms of our antibody that show a similar binding affinity as mAbner, recognize all or most recurrent (and primary) cancers, do not react with normal tissues, and can reduce the size of tumors, and/or prevent their growth in vivo. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer. PUBLIC HEALTH RELEVANCE: This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means lt 10% expected 5 year survival rate for patients representing gt 40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a newly discovered abnormal receptor which seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody to treat this deadly disease. This antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long-term survival rate for these patients.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.82K | Year: 2014

DESCRIPTION (provided by applicant): There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, MAG-1, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that a cancer -specific provasopressin antigen, called GRSA, present at the surface of these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by MAG-1 antibodies in combination with cyclophosphamide. Our preliminary data clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse MAG-1 significantly slows growth, but this growth is almost completely impaired when antibody treatment follows cyclophosphamide. GRSA expression is a feature common to all, or most, SCLC and is absent from normal tissues. Phase 1 of this study is directed at advancing treatment of rSCLC using both mouse MAG-1 and already generated human chimeric MAG-1 a


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2011

DESCRIPTION (provided by applicant): The objective of this Phase 1 project is to improve an effective treatment of recurrent small-cell lung cancer (rSCLC) by targeting a tumor-specific abnormal receptor, AbnV2 that is a surface-marker of the disease. Currently, there is no effective treatment for rSCLC. Our data show expression of this abnormal vasopressin V2 receptor (AbnV2 ) is a common feature of recurrent as well as primary cancers, and can be targeted by polyclonal and monoclonal antibodies recognizing unique features in a C-terminal extracellular domain. They are absent from normal tissues. Polyclonal Abs can inhibit in vitro the growth of cancer cells derived from recurrent as well as primary tumors. Expression of such receptors therefore not only raises the possibility to develop new and successful therapies for this disease, but also methods for detecting residual tumor and monitoring treatment. Such therapies should have particular relevance to recurrent disease. The hypothesis being tested is that the AbnV2 receptor will provide a sensitive and reliable target for effective treatment of recurrent rSCLC, and that monoclonal antibodies can serve as effective therapeutic targeting agents. Phase 1 goals are directed towards:(i) performing a 'proof ofprinciple' evaluation of the effectiveness of unmodified and/or 90Y-labeled anti-AbnV2 monoAb to destroy/prevent growth of variant (and recurrent disease derived) NCI H82 and classical (and primary tumor-derived) NCI H345 SCLC cells grown in athymic mice;(ii) establishing the distribution and abundance in SCLC tumors of AbnV2 receptor protein and its unique expression by these tumors, and;(iii) determining the ability of anti-AbnV2 monoAb to inhibit the growth of SCLC cells in culture, and exploring mechanisms through which growth inhibition is accomplished. Treatment with forms of anti-AbnV2 monoAb will be compared with ubiquitous immunoglobulin (MOPC21). These investigations are designed to employ, tumor targeting in a mouse model, cytofluorographic and radiometric quantitation, antibody modification, tumor growth assessments, assessment of apoptotic and necrotic changes, IHC, ELISA, RIA, flow cytometry, RT-PCR, DNA sequencing, and Western analysis with densiometric quantitation. The approach employed is considered innovative because it represents the first treatment of form of recurrent SCLC cancer with an unmodified tumor-specific antibody. It is also provides the possibility that treatment progress can be monitored by use of radio-labeled fragments of the same antibody. A successful end-point of our Phase 1 studies would be the clear determination that unmodified, and/or 90Yttrium-labeled, anti-AbnV2 antibody can destroy or significantly curtail the growth of SCLC tumors in vivo, and that AbnV2 is a marker for gt50% of SCLC tumors. Phase 2 would involve the preclinical testing of chimeric and humanized forms of anti-AbnV2 on SCLC. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer. rSCLC resists all current efforts at treatment. PUBLIC HEALTH RELEVANCE: This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means lt 10% expected 5 year survival rate for patients representing gt 40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a newly discovered abnormal receptor which seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody to treat this deadly disease. This antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long- term survival rate for these patients.


Patent
Woomera Therapeutics, Inc. | Date: 2014-05-12

Provided herein are pro-VP antagonists, such as antibodies and antigen-binding portions thereof specific for pro-VP, for identifying and targeting expressing cancer cells. Applicants additionally provide methods of using said compositions, for example to image cancer cells in vivo and in biological samples. The compositions may also be used for treating patients suffering from a provasopressin-expressing cancer. Provasopressin-expressing cancers include neuroendocrine cancer, pancreatic cancer, and prostate cancer.


Patent
Woomera Therapeutics, Inc. | Date: 2014-05-12

Provided herein are antagonists or binding agents of an abnormal vasopressin receptor V_(2 )(e.g., AbnV_(2)), such as antibodies and antigen-binding portions thereof specific for the receptor, for identifying and targeting cancer cells expressing such abnormal vasopressin receptor V_(2). Additionally provided are methods of using said antagonists or binding agents, for example, to image cancer cells or in biological samples, or diagnose cancers, both in vivo and in vitro. The antagonists or binding agents may also be used for treating patients suffering from a cancer expressing the abnormal vasopressin receptor V_(2), such as small cell lung cancer (SCLC), breast cancer, or ovarian cancer.

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