cancer-research

Bostad M, Berg K, Hogset A, Skarpen E, Stenmark H, Selbo PK (2013) Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties. J Control Release 168(3):317-326. doi: 10.1016/j.jconrel.2013.03.023

Summary: Targeted therapies for cancer can be trapped in the lysosome and compartmentalized away from the target. Photochemical internalization is a method to increase the efficacy of these compounds by releasing the therapeutic portion of the molecule from the endocytic vesicles to the cytosol by the use of light. The authors demonstrate this method on cells expressing the cancer stem cell marker CD133. Biotinylated antibodies against CD133 were combined with Streptavidin-ZAP (Cat. #IT-27) and applied to cell lines.

Related Products: Streptavidin-ZAP (Cat. #IT-27)

Burgos-Ojeda D, McLean K, Bai S, Pulaski H, Gong Y, Silva I, Skorecki K, Tzukerman M, Buckanovich RJ (2013) A novel model for evaluating therapies targeting human tumor vasculature and human cancer stem-like cells. Cancer Res 73(12):3555-3565. doi: 10.1158/0008-5472.CAN-12-2845

Objective: To evaluate tumor vascular markers (TVM) expression in a human embryonic stem cell–derived teratoma (hESCT) tumor model previously shown to have human vessels.

Summary: The model tested represents a useful tool to test anti-human TVM therapy and evaluate in vivo human CSC tumor biology.

Usage: In vitro – Anti-THY1-SAP (biotinylated Anti-THY1 mixed equimolar with Streptavidin-ZAP) was incubated with mesenchymal stem cells (MSC); resulting in statistically significant MSC death. In vivo – Anti-THY1-SAP or control (Rat IgG-SAP) was administered intravenously. Treated ovarian tumors showed delayed growth and significant reduction in central tumor viability.

Related Products: Streptavidin-ZAP (Cat. #IT-27), Rat IgG-SAP (Cat. #IT-17)

Daniotti JL (2013) Featured Article: Antibodies to glycosphingolipids: An attractive tool for targeted delivery of cytotoxic agents to tumor cells. Targeting Trends 14(2)

Related Products: Mab-ZAP (Cat. #IT-04)

Read the featured article in Targeting Trends.

See Also:

• Torres Demichelis V et al. Targeted Delivery of Immunotoxin by Antibody to Ganglioside GD3: A Novel Drug Delivery Route for Tumor Cells. PLoS One 8(1):e55304, 2013.

Rust S, Guillard S, Sachsenmeier K, Hay C, Davidson M, Karlsson A, Karlsson R, Brand E, Lowne D, Elvin J, Flynn M, Kurosawa G, Hollingsworth R, Jermutus L, Minter R (2013) Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type. Mol Cancer 12:11. doi: 10.1186/1476-4598-12-11

Summary: The authors investigated a phenotypic antibody screening technique, in which antibodies are selected by function rather than target specificity. One facet of the screening procedure for hybridomas generated using a cancer cell line as antigen was the use of Mab-ZAP (Cat. #IT-04) to assess cell binding and internalization.

Related Products: Mab-ZAP (Cat. #IT-04)

Torres Demichelis V, Vilcaes AA, Iglesias-Bartolome R, Ruggiero FM, Daniotti JL (2013) Targeted delivery of immunotoxin by antibody to ganglioside GD3: A novel drug delivery route for tumor cells. PLoS One 8(1):e55304. doi: 10.1371/journal.pone.0055304

Summary: The authors used the mouse monoclonal antibody R24 against ganglioside G3 with Mab-ZAP (Cat. #IT-04) to test the viability of ganglioside G3 as a cancer therapy target. Varying concentrations of R24 were used on various cell lines with either 0.95 nM or 9.5 nM Mab-ZAP depending on the cell line.

Related Products: Mab-ZAP (Cat. #IT-04)

Read the featured article in Targeting Trends.

Kato J, O’Donnell RT, Abuhay M, Tuscano JM (2012) Efficacy and toxicity of a CD22-targeted antibody-saporin conjugate in a xenograft model of non-Hodgkin’s lymphoma. Oncoimmunology 1(9):1469-1475. doi: 10.4161/onci.21815

Summary: CD22 is a B-cell-specific antigen found on many B-cell malignancies. It is not expressed by stem cell precursors, and is rapidly internalized when bound by an antibody. In this work, the authors use a custom conjugate of anti-CD22 (mAb HB22.7) and saporin in a cytotoxicity assay on non-Hodgkin’s lymphoma cell lines, as well as in a mouse tumor model. The dosing for the tumor model was 1 mg conjugate per kg of animal. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The results indicate that CD22 is a potential therapeutic target for cancer therapy.

Related Products: Mouse IgG-SAP (Cat. #IT-18), Custom Conjugates

Tuscano JM, Kato J, Pearson D, Xiong C, Newell L, Ma Y, Gandara DR, O’Donnell RT (2012) CD22 antigen is broadly expressed on lung cancer cells and is a target for antibody-based therapy. Cancer Res 72(21):5556-5565. doi: 10.1158/0008-5472.CAN-12-0173

Summary: The median overall survival of patients with advanced, unresectable, non-small cell lung cancer is 9-12 mos. A potential therapeutic target is CD22, a protein expressed on lung cancer cells. The authors examined the use of the monoclonal antibody HB22.7 as an antitumor agent. To assess internalization of the antibody, it was first incubated with 10 μg/ml Mab-ZAP (Cat. #IT-04) then applied to two different cancer cell lines in culture. Analysis of cell viability demonstrated that CD22 internalized when bound by the antibody-toxin complex, suggesting that targeting CD22 has therapeutic potential.

Related Products: Mab-ZAP (Cat. #IT-04)

Daniels-Wells TR, Helguera G, Rodriguez JA, Leoh LS, Erb MA, Diamante G, Casero D, Pellegrini M, Martinez-Maza O, Penichet ML (2013) Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1. Toxicol In Vitro 27(1):220-231. doi: 10.1016/j.tiv.2012.10.006

Summary: The antibody-avidin fusion protein ch128.1Av has been shown to target the human transferrin receptor 1 (TfR1) and kill malignant B cells by blocking the use of iron. Combination of this construct with a mono-biotinylated saporin custom conjugate produces an iron-independent toxicity to TfR1-expressing cells, even those that are resistant to ch128.1Av alone. The saporin-containing conjugate induces a transcriptional response consistent with oxidative stress and DNA damage. The data also show that the saporin conjugate is not toxic to human hematopoeietic stem cells.

Usage: An antibody-avidin fusion protein (ch128.1Av) was mixed with MonoBiotin-ZAP to make an immunotoxin that targets the human transferrin receptor 1 (TfR1).

Related Products: MonoBiotin-ZAP (Cat. #BT-ZAP), Custom Conjugates

Ye Y, Viet CT, Dang D, Schmidt BL (2012) IB4 (+) neurons contribute to force-induced cancer pain but not cancer proliferation. Neuroscience 2012 Abstracts 67.10. Society for Neuroscience, New Orleans, LA.

Summary: The primary treatment for cancer pain is μ-opiates; however, often μ-opiates are not effective and they produce multiple debilitating side effects. Recent studies show that μ- and δ-opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which mediate thermal and mechanical pain, respectively. We investigated the contribution of IB4 (+) and IB4 (-) neurons to cancer-induced mechanical and thermal hypersensitivity and investigated the role of these fibers to cancer proliferation. We used two separate mouse cancer pain models: 1) a cancer supernatant injection model, and 2) an orthotopic cancer model. The former model isolated the effect of the cancer secretome while the latter examined the effect of the following constituents within the cancer microenvironment: the cancer, the cancer secretome and the host tissue. Using the cancer supernatant model, along with injection of a selective δ-opioid receptor agonist and a P2X3 antagonist to target IB4 (+) neurons, we showed that IB4 (+) neurons played arole in cancer-supernatant-induced mechanical allodynia, but not thermal hyperalgesia. Selective ablation of IB4 (+) neurons in the spinal cord using IB4-saporin affected cancer-supernatant-induced mechanical but not thermal hypersensitivity. In the orthotopic cancer model, mice with paw cancer exhibited both mechanical and thermal hypersensitivity. Selective ablation of IB4(+) neurons decreased mechanical hypersensitivity; however thermal hypersensitivity was increased. We hypothesized that increased thermal hyperalgesia was associated with a compensatory elevation of TRPV1 expression in the spinal cord. Thermal latency in the mouse cancer paw was increased by intrathecal TRPV1 antagonist and selective removal of TRPV1 terminals by capsaicin in the IB4-saporin treated mice compared to saporin treated mice. Mechanical threshold was not affected by either the TRPV1 antagonist or capsaicin treatment. In the spinal cord, TRPV1 protein levels were increased in cancer mice compared to naïve mice, and TRPV1 was likely to be increased in the IB4-saporin treated cancer mice compared to saporin treated cancer mice. We investigated cancer proliferation by measuring tumor volume. Tumor volume was not affected by selective ablation of IB4 (+) neurons. Our findings suggest that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X3 antagonist, might be effective for treating cancer pain in patients. Acknowledgements: Supported by NIH/NIDCR R21 DE018561

Related Products: IB4-SAP (Cat. #IT-10)

Berstad MB, Weyergang A, Berg K (2012) Photochemical internalization (PCI) of HER2-targeted toxins: Synergy is dependent on the treatment sequence. Biochim Biophys Acta 1820(12):1849-1858. doi: 10.1016/j.bbagen.2012.08.027

Summary: A majority of patients develop acquired resistance to trastuzumab, the monoclonal antibody recognizing HER2, coupled to a toxin as a breast cancer therapeutic. One of the modes of resistance is that the therapeutic molecule is trapped inside an endocytic vesicle. PCI is a technique that facilitates cytosolic release of molecules in vesicles. The authors investigated the potency of biotinylated trastuzumab combined with streptavidin-ZAP (Cat. #IT-27) on several cell lines.

Related Products: Streptavidin-ZAP (Cat. #IT-27)