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Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2.

As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 Å crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.

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BioLineRx Announces Presentation of Detailed Mechanism of Action Data for Lead Oncology Platform at AACR 2016

On April 19, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX) reported that detailed results from a study on the underlying mechanism of action of BL-8040, its lead platform for the treatment of multiple cancer and hematological indications, were presented by Prof. Amnon Peled at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2016 meeting in New Orleans (Press release, BioLineRx, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158220 [SID:1234511046]).

The work presented, entitled "CXCR4 Controls BCL-2 Expression and Function by Regulating miR-15a/16-1 Expression in Tumor Cells," illustrates the mechanism by which the CXCR4 pathway controls malignant cell survival and death in preclinical studies. Specifically, the studies point out how BL-8040 increases the expression and activity of a special class of microRNA precursors termed miR-15a/16-1. These microRNA molecules have been previously linked to cancer, and shown to suppress the activity of several tumor-related pro-survival proteins, specifically BCL2, MCL1 and cyclin D1. The studies presented showed that BL-8040 increases the suppression of these three target proteins through miR-15a/16-1, thereby increasing tumor cell death.

The BL-8040 oncology platform is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is overexpressed in the majority of cancer cells, and its degree of expression often correlates with disease severity.

Dr. Kinneret Savitsky, CEO of BioLineRx, stated, "We recently announced the successful top-line results for BL-8040, in combination with Cytarabine, one of the standard-of-care chemotherapies, in a Phase 2 study in relapsed or refractory AML. In that study, BL-8040 showed a triple effect on the leukemic cells. First, BL-8040 monotherapy triggered robust mobilization of AML cells from the bone marrow to the peripheral blood, thereby sensitizing these cells to the chemotherapy and improving its efficacy. Second, BL-8040 monotherapy showed a 3-4 fold increase in the direct apoptotic effect on the leukemia cells in the bone marrow. Last, BL-8040 monotherapy induced leukemia progenitor cells towards differentiation. As a result of these factors, we reported a 38% complete remission rate in the study, compared to historical remission rates in similar patient populations with similar treatment regimens of approximately 20% for Cytarabine on a stand-alone basis. We look forward to providing the full results of this study at an upcoming scientific conference."

"In this regard, we are pleased to announce the current study results presented at the AACR (Free AACR Whitepaper) meeting, which provide significant clarity regarding BL-8040’s mechanism of action relating to apoptosis. The data suggest that BL-8040 is able to indirectly suppress the activity of several tumor-promoting genes, by increasing the activity of the microRNA molecule miR-15a/16-1. Of note, one of these pro-survival proteins, BCL-2, is a validated anti-cancer target that is recently attracting a lot of interest in the drug development space."

"In order to further expand and enhance the potential of our unique oncology platform, BL-8040 is undergoing multiple clinical studies, including our recently announced immuno-oncology collaboration with Merck on a Phase 2 study to investigate BL-8040 in combination with KEYTRUDA for the treatment of pancreatic cancer," concluded Dr. Savitsky.

Link to AACR (Free AACR Whitepaper) On-Line Abstract

About BL-8040
BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem-cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem-cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.

BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 also significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the recently completed Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells, along with a clinically meaningful response rate. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

AACR Research Reception Featured Late-Breaking Poster on Lm Technology™ Platform

On April 19, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, hosted a Research Reception on Monday, April 18, 2016 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Advaxis, APR 19, 2016, View Source [SID:1234511045]).

The Research Reception featured Rosemarie Krupar, M.D., of Baylor College of Medicine, presenting "Immunogenicity of Axalimogene Filolisbac in Head and Neck Cancer," a review of the late-breaking poster presentation (Abstract #LB-095). The phase 2 trial leveraged a 5-6 week window between diagnosis and trans-oral robotic surgery, administering two doses of treatment with Advaxis’ lead immunotherapy candidate, axalimogene filolisbac (AXAL), two weeks apart to eight patients with late-stage HPV-associated oropharyngeal cancer (HPVOPC). The study observed changes to the tumor immune microenvironment (TME), including cytotoxic T cell infiltration into the post-resection tumor, increased immune activation, a reduction of regulatory T cells, infiltration of cytotoxic T cells, and increased expression of inflammatory activation markers, suggesting that AXAL has the potential to cause positive immunologic responses for patients with HPV+ head and neck cancers.

Nicola Mason, Ph.D., BVetMed, Assistant Professor of Medicine at the University of Pennsylvania, presented "Immune Therapy with ADXS31-164 Prevents Metastatic Disease and Prolongs Overall Survival in Spontaneous Canine Osteosarcoma." In her presentation, Dr. Mason reviewed her experiences with ADXS31-164 in dogs with spontaneous osteosarcoma. In two separate studies, repeat administrations of up to 3.3 x 109 CFUs were well tolerated with transient low-grade side effects. Immune responses to HER2/neu were detected within 6 months in 15 of 18 dogs with minimal residual disease. In these dogs, metastatic disease was delayed or prevented. Radiographic progression of primary osteosarcoma lesions was prevented in a subset of dogs who were treated after palliative radiotherapy. Treated animals had tumor-specific T-cell responses in the tumor site and reduced numbers of Tregs and MDSCs in the tumor microenvironment.

Robert Petit, Ph.D., Chief Scientific Officer and EVP of Advaxis, presented "Effect of Advaxis’ Lm Immunotherapy on the STING Pathway." In his presentation, Dr. Petit discussed the potent triggering of STING (STimulator of Interferon Genes) built into every Advaxis vector and triggered by DNA, including 80-100 copies of DNA plasmids, that code for tumor target antigens. Advaxis Lm-LLO vectors escape into the cytosol of antigen-presenting cells (APCs) where the human STING receptor is triggered preferentially by DNA. Triggering STING results in the secretion of type I interferons and pro-inflammatory cytokines and has been linked to immune sensing of tumors, clinical responses to melanoma, and inflammation of the tumor microenvironment. Experiments in STING knock-out models demonstrate that triggering of STING contributes to part, but not all, of the ability of ADXS11-001 to control HPV+ tumors.

The Research Reception concluded with a final presentation by Robert Petit, "Cancer Neoepitope Immunotherapy: An Update on ADXS-NEO." Advaxis’ Lm Technology is being used to develop novel ADXS-NEO immunotherapies personalized to the specific and unique neo-epitopes found in an individual patient’s tumor. ADXS-NEO is projected to be available for patients in 6-8 weeks from biopsy to infusion. This platform is able to decrease Tregs and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and can be used to combine tumor driver targets along with neoepitope targets. Data was presented from a mouse model, demonstrating the ability of ADXS-NEO to express multiple tumor neoantigens which were capable of controlling tumor growth. The data developed in this model confirms that ADXS-NEO can be successfully executed and administered and has the ability to control the tumors that were the source of the neoantigens. Advaxis is currently developing an Investigational New Drug Application for ADXS-NEO and is planning for upcoming clinical trials.

Advaxis is actively building collaborations in academia and industry to drive ADXS-NEO forward, including the MINE (My Immunotherapy Neo-Epitopes) collaboration with Memorial Sloan Kettering Cancer Center, focusing on preclinical and clinical development of neoepitope-based Lm treatments. The goal of MINE is to develop neo-epitope immunotherapies based on the specific and unique neo-epitopes found in an individual patient’s tumor. Advaxis is currently partnering with SGI-DNA for DNA synthesis and bioinformatics.

To view the presentation slides and to listen to the presenters, visit www.advaxis.com.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. Axalimogene filolisbac has Orphan Drug Designation in the U.S. for the treatment of anal cancer.

Endocyte Announces Promising Preclinical Data for Application of SMDC Technology in CAR T Cell Therapy in Late-Breaking Abstract at American Association for Cancer Research (AACR) Annual Meeting 2016

On April 19, 2016 Endocyte, Inc. (NASDAQ:ECYT), a leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, reported in a late-breaking poster session the presentation of new research from investigators and faculty at the Purdue University Center for Drug Discovery on the application of Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting (Poster #LB-254 – A Universal Remedy for CAR T cell limitations) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Endocyte, APR 19, 2016, View Source [SID:1234511043]).

"This technology and these data reflect a potentially significant advance in overcoming several challenges specific to CAR therapies as well as the powerful versatility of Endocyte’s SMDC platform," said Ron Ellis, president and CEO at Endocyte. "This is still in the early stages of research, and we look forward to our continued collaboration with Phil Low and his lab at the Purdue Drug Discovery Center to further explore the potential of this CAR therapeutic approach as we look to build our SMDC platform in immuno-oncology."

The presentation discusses a novel approach that makes possible the engineering of a single universal CAR T cell, which binds with extraordinarily high affinity to a benign molecule designated as FITC. These cells are then used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to precisely bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation. Data in this poster show that anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Findings also show that anti-tumor activity and toxicity can be sensitively controlled by adjusting the dosing of the administered adaptor molecule. Furthermore, treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors. Thus, several challenges of current CAR T cell therapies, such as i) the inability to control the rate of cytokine release and tumor lysis, ii) the absence of an "off switch" that can terminate cytotoxic activity when tumor eradication is complete, and iii) a requirement to generate a different CAR T cell for each unique tumor antigen, may be solved or mitigated using this novel universal CAR T cell approach.

"Through our strong, ongoing collaboration with Endocyte, we are optimistic that this exciting approach might advance the enormous potential of CAR T cell therapies to benefit patients in truly meaningful ways," said Phil Low, Ph.D., professor of chemistry and director of the Center for Drug Discovery at Purdue University. Dr. Low is the chief scientific officer, a board member and founder of Endocyte.

Endocyte and Purdue University have an exclusive agreement to research, develop and commercialize SMDC therapeutics and companion imaging agents for the treatment of disease through a long-standing partnership with Dr. Low and Purdue University. Endocyte holds the global rights to the CAR and SMDC adaptors for all indications. Additionally, Endocyte and Purdue University jointly own this technology, which is covered by both allowed and pending patent applications.

Sensitive ELISA Method for the Measurement of Catabolites of Antibody-Drug Conjugates (ADCs) in Target Cancer Cells.

A new, sensitive ELISA method has been developed which measures catabolites in cells and media upon processing of antibody-drug conjugates (ADCs) by target cancer cells. This ELISA method, exemplified for maytansinoid ADCs, uses competitive inhibition by a maytansinoid analyte of the binding of biotinylated antimaytansine antibody to an immobilized BSA-maytansinoid conjugate. Synthetic standards of several maytansinoid catabolites derived from ADCs with different linkers were tested and showed similar inhibition curves, with an EC50 of about 0.1 nM (0.03 pmol in an assay volume of 0.25 mL). This high sensitivity allowed quantification of catabolites from a methanolic cell extract and from the medium, generated from an ADC in 1 day using only about 1 million cells. The processing of anti-EpCAM and anti-CanAg ADCs with noncleavable linker (SMCC-DM1), disulfide linker (SPDB-DM4), and charged sulfonate-bearing disulfide linker (sulfo-SPDB-DM4), each containing an average of about four maytansinoid molecules per antibody, were compared in colon cancer cell lines (COLO 205 and HT-29). An 8-10-fold higher total level of catabolite was observed for anti-CanAg ADCs than for anti-EpCAM ADCs upon processing by COLO 205 cells, consistent with a higher cell-surface expression of CanAg. In a multidrug resistant HCT-15 colon cancer cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was not cytotoxic and showed a significantly lower level of catabolite within cells compared to that in medium, presumably due to Pgp-mediated efflux of the nonpolar DM4 catabolite. In contrast, sulfo-SPDB-DM4 and SMCC-DM1 linker conjugates were cytotoxic, which correlated with higher amounts of catabolites found within the HCT-15 cells relative to amounts in medium. In a nonmultidrug resistant HT-29 cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was cytotoxic, with most of the catabolite found in cells and little in the medium. In conclusion, this highly sensitive ELISA method for measurement of ADC catabolite is convenient for screening multiple ADC parameters such as linkers and antibodies in a number of cell lines, does not require concentration of sample or extraction of media, and is complementary to other reported methods such as radiolabeling of ADCs or mass spectrometry.