The Experts below are selected from a list of 82623 Experts worldwide ranked by ideXlab platform
Heide Schatten - One of the best experts on this subject based on the ideXlab platform.
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immunodiagnostics and immunotherapy possibilities for prostate Cancer
Advances in Experimental Medicine and Biology, 2018Co-Authors: Heide SchattenAbstract:Despite significant progress in early detection and improved treatment modalities prostate Cancer remains the second leading cause of Cancer death in American men which results in about 30,000 deaths per year in the USA. An aggressive phenotype leading to 2.58% risk of dying from prostate Cancer still exists and immunotherapy has offered new possibilities to treat metastatic prostate Cancer that cannot be treated by other modalities. Cancer immunotherapy is a rapidly growing field of research aimed at identifying biomarkers in immunodiagnosis and to develop new therapies by enabling the immune system to detect and destroy Cancer cells. Immunotherapy falls into three different broad categories which are checkpoint inhibitors, cytokines, and vaccine immunotherapy. While immunotherapy to treat prostate Cancer is still limited progress has been made; for treatment of advanced prostate Cancer sipuleucel-T has been administered to patients in personalized doses to destroy prostate Cancer cells which is promising and invites further research to determine immunotherapies for advanced prostate Cancer. Antibody-based targeted immunotherapy and dendritic-cell-based vaccination are among the therapies that are currently being evaluated as promising approaches to treat prostate Cancer. Combination immunotherapies include prostate Cancer vaccines and radiotherapy for castration resistant prostate Cancer. Microbial vectors for prostate Cancer immunotherapy have been developed and bacterial strains have been engineered to express Cancer-specific antigens, cytokines, and prodrug-converting cytokines. These approaches are addressed in the present review.
Susan Hahn - One of the best experts on this subject based on the ideXlab platform.
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anti cd9 Antibody ar40a746 2 3 inhibits tumor growth in pancreatic and breast Cancer models and recognizes cd9 on cd34 cd38 leukemic Cancer stem cells
Cancer Research, 2008Co-Authors: Javier Menendez, Liqing Jin, Armando Poeppl, Daad Sayegh, Kevin Oreilly, Nives Ceric, Tejal B Vyas, Ashwani K Gupta, Susan Hahn, David M YoungAbstract:3993 CD9 is a 24 kDa member of the transmembrane 4 (TM4) family that is expressed on both normal tissues as well as a variety of solid and liquid tumors. Tetraspanins interact with other tetraspanins, integrins and assorted receptors in a variety of physiological processes that include immune cell activation, cell migration, cell-cell fusion and various aspects of cellular differentiation and proliferation. Using the ARIUS FunctionFIRST™ anti-Cancer Antibody discovery platform, we have generated a monoclonal Antibody, AR40A746.2.3, targeting human CD9. This Antibody induces cytotoxicity in a variety of solid tumor cell lines invitro. It also inhibits tumor growth in both prophylactic and established xenograft models of human pancreatic and breast Cancer. In a prophylactic and established BxPC-3 model of pancreatic Cancer, tumor growth was inhibited by 100% (p
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ar47a6 4 2 a naked monoclonal Antibody targeting trop 2 exhibits anti tumor efficacy in multiple human Cancer models as a monotherapeutic agent and demonstrates efficacy in combination therapy
Cancer Research, 2008Co-Authors: Amandine Truong, Daad Sayegh, Susan Hahn, Ningping Feng, Baldwin Mak, Daniel S Pereira, David YoungAbstract:3990 Trop-2 is a putative signal transduction molecule with widespread expression reported in a number of human carcinomas. Increasing evidence supports the role of Trop-2 in Cancer, and over-expression studies suggest Trop-2 plays a role in Cancer cell proliferation both in vitro and in vivo. In human colorectal Cancer, high levels of Trop-2 have been associated with poor prognosis and a decrease in patient survival. Most recently, Trop-2 was suggested to play an important role in metastasis and high levels of Trop-2 were reported in metastatic tumors from breast Cancer patients. Taken together, these findings suggest that targeting Trop-2 in Cancer patients may be an effective therapeutic strategy. Using the ARIUS FunctionFIRST™ anti-Cancer Antibody discovery platform, AR47A6.4.2, a functional monoclonal Antibody targeting human Trop-2, was identified. To examine the potential anti-tumor effect of this Antibody in vivo, AR47A6.4.2 was administered in both prophylactic and established xenograft models of human solid tumors. Significant tumor growth inhibition was observed in models of breast, pancreatic, colon, and prostate Cancers, concomitant with an increase in the survival of mice in the Antibody treatment groups. The potency of AR47A6.4.2 was enhanced in an established model of pancreatic Cancer when administered in combination with Gemcitabine®, a standard of care in pancreatic Cancer. The combination therapy resulted in tumor regression during the treatment period, and 97 % tumor growth inhibition was observed 27 days after treatment ended. Mechanism of action studies have revealed that AR47A6.4.2 treatment diminishes MAPK phosphorylation in response to serum stimulation, suggesting that AR47A6.4.2 may exert some of its anti-tumor effects by inhibiting TROP-2 signaling and downstream phosphorylation of MAPK. In addition, in pancreatic Cancer cell lines where AR47A6.4.2 has exhibited anti-tumor activity, AR47A6.4.2 was also shown to induce complement dependent cytotoxicity in vitro. In summary, AR47A6.4.2, the first naked therapeutic Antibody targeting Trop-2, demonstrates significant anti-tumor in vivo efficacy in xenograft models of human pancreatic, colon, breast and prostate Cancer, thereby confirming its potential therapeutic value in treating these solid tumor malignancies. In addition, this Antibody can be combined with chemotherapy to enhance its anti-tumor activity. Towards the goal of bringing AR47A6.4.2 to the clinic, the cynomolgus monkey has been identified as a relevant pre-clinical toxicology model and a humanized version of AR47A6.4.2 has been generated with high affinity and potent anti-tumor activity.
Daad Sayegh - One of the best experts on this subject based on the ideXlab platform.
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anti cd9 Antibody ar40a746 2 3 inhibits tumor growth in pancreatic and breast Cancer models and recognizes cd9 on cd34 cd38 leukemic Cancer stem cells
Cancer Research, 2008Co-Authors: Javier Menendez, Liqing Jin, Armando Poeppl, Daad Sayegh, Kevin Oreilly, Nives Ceric, Tejal B Vyas, Ashwani K Gupta, Susan Hahn, David M YoungAbstract:3993 CD9 is a 24 kDa member of the transmembrane 4 (TM4) family that is expressed on both normal tissues as well as a variety of solid and liquid tumors. Tetraspanins interact with other tetraspanins, integrins and assorted receptors in a variety of physiological processes that include immune cell activation, cell migration, cell-cell fusion and various aspects of cellular differentiation and proliferation. Using the ARIUS FunctionFIRST™ anti-Cancer Antibody discovery platform, we have generated a monoclonal Antibody, AR40A746.2.3, targeting human CD9. This Antibody induces cytotoxicity in a variety of solid tumor cell lines invitro. It also inhibits tumor growth in both prophylactic and established xenograft models of human pancreatic and breast Cancer. In a prophylactic and established BxPC-3 model of pancreatic Cancer, tumor growth was inhibited by 100% (p
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ar47a6 4 2 a naked monoclonal Antibody targeting trop 2 exhibits anti tumor efficacy in multiple human Cancer models as a monotherapeutic agent and demonstrates efficacy in combination therapy
Cancer Research, 2008Co-Authors: Amandine Truong, Daad Sayegh, Susan Hahn, Ningping Feng, Baldwin Mak, Daniel S Pereira, David YoungAbstract:3990 Trop-2 is a putative signal transduction molecule with widespread expression reported in a number of human carcinomas. Increasing evidence supports the role of Trop-2 in Cancer, and over-expression studies suggest Trop-2 plays a role in Cancer cell proliferation both in vitro and in vivo. In human colorectal Cancer, high levels of Trop-2 have been associated with poor prognosis and a decrease in patient survival. Most recently, Trop-2 was suggested to play an important role in metastasis and high levels of Trop-2 were reported in metastatic tumors from breast Cancer patients. Taken together, these findings suggest that targeting Trop-2 in Cancer patients may be an effective therapeutic strategy. Using the ARIUS FunctionFIRST™ anti-Cancer Antibody discovery platform, AR47A6.4.2, a functional monoclonal Antibody targeting human Trop-2, was identified. To examine the potential anti-tumor effect of this Antibody in vivo, AR47A6.4.2 was administered in both prophylactic and established xenograft models of human solid tumors. Significant tumor growth inhibition was observed in models of breast, pancreatic, colon, and prostate Cancers, concomitant with an increase in the survival of mice in the Antibody treatment groups. The potency of AR47A6.4.2 was enhanced in an established model of pancreatic Cancer when administered in combination with Gemcitabine®, a standard of care in pancreatic Cancer. The combination therapy resulted in tumor regression during the treatment period, and 97 % tumor growth inhibition was observed 27 days after treatment ended. Mechanism of action studies have revealed that AR47A6.4.2 treatment diminishes MAPK phosphorylation in response to serum stimulation, suggesting that AR47A6.4.2 may exert some of its anti-tumor effects by inhibiting TROP-2 signaling and downstream phosphorylation of MAPK. In addition, in pancreatic Cancer cell lines where AR47A6.4.2 has exhibited anti-tumor activity, AR47A6.4.2 was also shown to induce complement dependent cytotoxicity in vitro. In summary, AR47A6.4.2, the first naked therapeutic Antibody targeting Trop-2, demonstrates significant anti-tumor in vivo efficacy in xenograft models of human pancreatic, colon, breast and prostate Cancer, thereby confirming its potential therapeutic value in treating these solid tumor malignancies. In addition, this Antibody can be combined with chemotherapy to enhance its anti-tumor activity. Towards the goal of bringing AR47A6.4.2 to the clinic, the cynomolgus monkey has been identified as a relevant pre-clinical toxicology model and a humanized version of AR47A6.4.2 has been generated with high affinity and potent anti-tumor activity.
Ashleigh Stewart - One of the best experts on this subject based on the ideXlab platform.
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abstract 2901 gastric Cancer Antibody fragment drug conjugates fdcs from concept to clinical development
Cancer Research, 2020Co-Authors: Mahendra Deonarain, Gokhan Yahioglu, Ioanna Stamati, Bryan M Edwards, Soraya Diezposada, Anja Pomowski, Isabel Perezcastro, Ben Stenton, Laura Bouche, Ashleigh StewartAbstract:Antibody Drug Conjugates (ADCs) are failing due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. The industry is full of approaches where full-length Immunoglobulins have been engineered to carry defined numbers of payloads with higher-loadings of less potent payloads appearing to be well-tolerated. However, Antibody fragments (e.g. single-chain Fcs-scFvs), which have many advantages including rapid tumour penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favourable biophysical properties, leading to a new product class tailored for solid tumours. Antikor has two FDC products in development for solid tumours, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045) which will be disclosed during this presentation. ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumour ablation effects in breast, ovarian and gastric Cancer xenograft models and superior tolerability compared to an ADC in rat toxicology studies at a dose of 1mg/kg/weekly. Tumour uptake and fluorescent immuno-histological studies demonstrate superior solid tumour penetration across the entire tumour and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology, Antikor is taking ANT-043 into IND-enabling studies for clinical development. In a new development, ANT-045, which emerged from Antikor9s proprietary FDC phage-display ‘discovery engine9, is progressing well and new data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal Cancers. Like ANT-043, our follow-up product has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and biophysical properties and illustrates how linker-payload modification (size, hydrophilicity) is critical for the tailoring of the binding and pharmacokinetic properties of this emerging format of ADC. This presentation will focus on Antikor9s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate a new products for difficult to treat solid tumours for patient benefit and promising to succeed where ADCs have failed to deliver. Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, ioanna Stamati, Bryan Edwards, Soraya Diez-Posada, Anja Pomowski, Isabel Perez-Castro, Ben Stenton, Laura Bouche, Ashleigh Stewart, Malcolm Ngiam, Quinn Xue. Gastric Cancer Antibody fragment drug-conjugates (FDCs): From concept to clinical development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2901.
Kaori Hiraga - One of the best experts on this subject based on the ideXlab platform.
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a cell based internalization and degradation assay with an activatable fluorescence quencher probe as a tool for functional Antibody screening
Journal of Biomolecular Screening, 2015Co-Authors: Peter Corbett Liu, Yang Shen, Marshall Davenport Snavely, Kaori HiragaAbstract:For the development of therapeutically potent anti-Cancer Antibody drugs, it is often important to identify antibodies that internalize into cells efficiently, rather than just binding to antigens on the cell surface. Such antibodies can mediate receptor endocytosis, resulting in receptor downregulation on the cell surface and potentially inhibiting receptor function and tumor growth. Also, efficient Antibody internalization is a prerequisite for the delivery of cytotoxic drugs into target cells and is critical for the development of Antibody–drug conjugates. Here we describe a novel activatable fluorescence–quencher pair to quantify the extent of Antibody internalization and degradation in the target cells. In this assay, candidate antibodies were labeled with a fluorescent dye and a quencher. Fluorescence is inhibited outside and on the surface of cells, but activated upon endocytosis and degradation of the Antibody. This assay enabled the development of a process for rapid characterization of candidate antibodies potentially in a high-throughput format. By employing an activatable secondary Antibody, primary antibodies in purified form or in culture supernatants can be screened for internalization and degradation. Because purification of candidate antibodies is not required, this method represents a direct functional screen to identify antibodies that internalize efficiently early in the discovery process.