This study combined physical data from synchrotron SAXS, FTIR and microscopy with in-silico molecular structure predictions and mathematical modeling to examine inulin adjuvant particle formation and structure. The results show that inulin polymer chains adopt swollen random coil in solution. As precipitation occurs from solution, interactions between the glucose end group of one chain and a fructose group of an adjacent chain help drive organized assembly, initially forming inulin ribbons with helical organization of the chains orthogonal to the long-axis of the ribbon. Subsequent aggregation of the ribbons results in the layered semicrystalline particles previously shown to act as potent vaccine adjuvants. γ-Inulin adjuvant particles consist of crystalline layers 8.5nm thick comprising helically organized inulin chains orthogonal to the plane of the layer. These crystalline layers alternate with amorphous layers 2.4nm thick, to give overall particle crystallinity of 78%.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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On April 17, 2016 Jounce Therapeutics, Inc., a company focused on the discovery and development of novel cancer immunotherapies coupled to patient enrichment strategies,reported that they have presented new preclinical data from two programs in the company’s immuno-oncology pipeline at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Jounce Therapeutics, APR 17, 2016, View Source [SID:1234511009]). The data presented represent the broad applicability of Jounce’s Translational Science Platform.

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ICOS Program
Jounce’s first presentation highlighted JTX-2011, a humanized ICOS (inducible costimulator molecule) agonist antibody being developed for the treatment of solid tumors. JTX-2011 has a dual mechanism of action, stimulating T effector cells and selectively reducing intra-tumoral T regulatory cells, thereby shifting the balance of T cells in a tumor toward anti-tumor activity. JTX-2011 has demonstrated durable anti-tumor efficacy in multiple preclinical tumor models as both a single agent and in combination with anti-PD-1 therapy. Today’s presentation provides preclinical data on JTX-2011, including evaluation of JTX-2011 in non-human primates, in which the antibody was shown to be well tolerated.

Jounce plans to file an investigational new drug application for JTX-2011 in mid-2016 and commence clinical trials evaluating JTX-2011 both as a monotherapy cancer immunotherapeutic and in combination with other immunotherapies for solid tumors in the second half of 2016.

Beyond T Cell Program
Beyond the JTX-2011 lead program, Jounce has utilized its Translational Science Platform to characterize the immune cell type infiltrate in human tumors in a large scale analysis. Using an immune cell type signature approach, tumors are characterized by the prevalence of a particular immune cell type, facilitating relevant target prioritization of that cell type and coordinated biomarker identification of those tumors. Jounce is applying this strategy to multiple immune cell types, including immuno-suppressive macrophages.

Today’s presentation demonstrates that TIM-3 and LILRB2, a novel protein-to-protein binding pair on human macrophages, discovered through this platform, may provide a new therapeutic opportunity to convert immune-suppressive macrophages to immuneenhancing macrophages. Jounce researchers were able to identify a specific "myeloid functional" epitope (the defined segment of the TIM-3 protein to which the antibody binds). In in vitro assays, only the antibodies directed to this epitope converted macrophages to a more immune active, anti-tumor type. While the "myeloid functional" anti-TIM-3 antibodies did not directly affect T cells, targeting TIM-3 on myeloid cells in this manner did have a secondary, stimulatory effect on the adaptive immune system.

"Our Beyond T Cell programs are based on the importance of targeting different immune cells types, outside of the T cell," said Deborah Law, D. Phil., chief scientific officer, Jounce. "It is our belief that this approach will allow us to pursue tumor types not currently served by therapies that target adaptive immune cells by potentially converting the tumor microenvironment from an immune-suppressive state to an immune activating, anti-tumor state. We are tremendously excited to present the first data from this program today as we work to develop myeloid-functional TIM-3 antibodies to expand the potential immunotherapeutic approaches beyond T cells. We think this approach has the potential to bring the benefits of immunotherapy to patients that are not responsive to current immunotherapies."
About the Jounce Translational Science Platform Jounce is working to develop therapies that enable the immune system to attack tumors, thereby bringing long-lasting benefits to patients. Jounce has developed its Translational Science Platform to use an unbiased bioinformatics-based approach to interrogate particular cell types within the human tumor microenvironment (the cellular environment that makes up a tumor). This platform is designed to prioritize targets and identify related biomarkers to match the right therapy to the right patients.

On April 17, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported novel antibody-drug conjugate (ADC) technology advances presented at the 107th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held April 16 through 20, 2016 in New Orleans, LA (Press release, Seattle Genetics, APR 17, 2016, View Source;p=RssLanding&cat=news&id=2157672 [SID:1234510959]). Data in multiple presentations demonstrate the company’s leadership and innovation in the field of ADCs. Presentations will showcase a new auristatin-based drug-linker as well as several novel linkers that expand Seattle Genetics’ proprietary ADC technology platform and may enable application of previously inaccessible cytotoxic payloads.

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"We have a comprehensive scientific understanding of the multiple components necessary to develop antibody-drug conjugates for the potential treatment of hematologic malignancies and solid tumors," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Our data presentations at the AACR (Free AACR Whitepaper) Annual Meeting illustrate novel linker systems and cell-killing payloads as well as continued progress in understanding the chemical and biological properties of ADCs to inform potential future development. We believe ADCs will continue to play an increasingly important role in cancer treatment."

ADCs are monoclonal antibodies designed to deliver cytotoxic agents selectively to tumor cells. Seattle Genetics has developed proprietary technology employing synthetic cytotoxic agents and stable linker systems that attach these cytotoxic agents to the antibody. Seattle Genetics’ linker systems are designed to be stable in the bloodstream and release the potent cell-killing agent once inside targeted cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

Multiple oral and poster presentations are being featured at AACR (Free AACR Whitepaper) that highlight Seattle Genetics’ ADC technology advances. Abstracts can be found at www.aacr.org and include the following:

Three poster presentations on Sunday and Monday, April 17 and 18, 2016 (Abstracts #0351, 1285, 2082) will highlight the role of the tumor microenvironment in ADC clearance, antitumor activity and uptake. Importantly, preclinical data demonstrate the potential for tumor associated macrophages to contribute to antitumor activity through release of MMAE.
The development of novel quaternary ammonium linkers for the stable conjugation and efficient release of tertiary amine-containing payloads will be presented in a poster presentation on Monday, April 18, 2016 (Abstract #2056). Preliminary data demonstrate that this technology enables the evaluation of drug classes previously inaccessible as ADCs, including auristatin E and tubulysin.

The development of a novel methylene-alkoxy-carbamate (MAC) linker that enables direct conjugation of drugs through alcohol functional groups will be presented in an oral presentation at 3:50 p.m. ET on Tuesday, April 19, 2016 (Abstract #4334). This linker has the potential to expand the types of payloads utilized in ADCs.
Data from a novel monomethyl auristatin E (MMAE) linker technology will be highlighted in a poster presentation on Tuesday, April 19, 2016 (Abstract #2956). By incorporating a short polyethylene glycol (PEG) unit, a self-hydrolysing maleimide and a glucuronidase release mechanism, the new MMAE drug-linker demonstrates pronounced activity with an increased therapeutic index in preclinical models.

On April 17, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that Phase I data from its investigational agent talazoparib, a highly-potent PARP inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans by the study’s lead investigator Zev A. Wainberg, M.D., Associate Professor of Medicine at the University of California Los Angeles (UCLA) and Co-Director of the UCLA GI Oncology Program, during a Clinical Trials Mini-Symposium (Press release, Medivation, APR 17, 2016, View Source [SID:1234510958]). The primary objective of the study was to determine the maximum tolerated dose (MTD) of talazoparib in combination with either low-dose temozolomide or low-dose irinotecan in heavily pretreated patients with advanced malignancies.

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The data from the 40 patient trial demonstrated that combination treatment with talazoparib and low-dose chemotherapy resulted in stable disease or an objective response in 23 of 40 heavily pretreated patients with a variety of advanced cancers (clinical benefit rate of 58%). Most notably, objective responses were seen in four of seven (57%) heavily pre-treated non-BRCA-mutated ovarian cancer patients when talazoparib was used in combination with either low-dose temozolomide or low-dose irinotecan. Six of seven individuals (86%) with non-BRCA ovarian cancer had clinical benefit (four partial responses and two stable disease) and had a reduction in CA 125 levels by 50% or greater.

Importantly, the overall study demonstrated responses to combination talazoparib/low-dose chemotherapy in patients with multiple tumor types in which specific deleterious mutations in certain DNA repair genes extended beyond BRCA deficiency, including one patient who did not meet the criteria of having homologous recombination deficiency (HRD). These effects may be mediated through PARP inhibition, as well as enhanced PARP trapping, which interferes with the tumor cell’s ability to replicate DNA by locking PARP molecules onto the DNA strand.

"In non-clinical studies, talazoparib has been shown to have high potency specifically against PARP 1 and 2, and antitumor effects in various solid tumors. With these new results, we now have evidence in humans that suggests talazoparib in combination with low-dose chemotherapy is active in tumors with defects in DNA repair beyond BRCA deficiency, and possibly in patients without evidence of HRD. We feel these data are consistent with talazoparib’s potent PARP trapping ability, which we believe makes talazoparib a unique and exciting product candidate with the potential to be used in combination with DNA damaging therapies across a wide variety of tumor types," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "With more than half of the ovarian cancer patients demonstrating an objective response, particularly in a heavily pre-treated patient population with advanced disease, these findings are encouraging and support further evaluation of the safety and efficacy of talazoparib."

Talazoparib currently is in Phase III development for patients with locally advanced and/or metastatic breast cancer who harbor a germline BRCA1/2 mutation. It is also being studied in several investigator-sponsored trials across multiple tumor types.

The Phase I investigator-sponsored study evaluated escalating doses of talazoparib ( ≥ 0.5 mg given orally once daily) with either temozolomide ( ≥ 25 mg/m2 given orally on days 1-5; Arm A) or irinotecan ( ≥ 25 mg/m2 given by intravenous infusion every two weeks; Arm B) every 28 days in patients with advanced malignancies. Study participants ranged in age from 21 to 77 years (median: 57 years) and had received one to 15 prior chemotherapy regimens (median: 6). The primary endpoint of the study was the determination of the MTD. Secondary endpoints included pharmacokinetics, tumor response and biomarkers.

A total of 40 patients received escalating doses of talazoparib (0.5-1.0 mg) and either temozolomide or irinotecan (18 patients in Arm A and 22 in Arm B). Results showed the MTD for talazoparib was 1.0 mg. and 37.5 mg/m2 for either temozolomide or irinotecan when combined with 1.0 mg talazoparib. Partial responses were seen in four of seven (57%) germline BRCA wild type ovarian cancer patients who were platinum-resistant. Additional responses were seen in one patient each with Ewing’s Sarcoma, cervical adenocarcinoma, small cell lung cancer, and triple negative breast cancer. An association was observed between response and the presence of deleterious somatic mutations in DNA repair genes (PALB2 and RAD51D) distinct from BRCA mutations.

The most common grade 3/4 adverse events ( ≥ 5%) observed in patients treated with talazoparib plus temozolomide were neutropenia (28%), anemia (33%), and thrombocytopenia (33%). Among those treated with talazoparib plus irinotecan, the most common adverse events were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant pharmacokinetic interactions were observed between talazoparib and either temozolomide or irinotecan.

About Talazoparib
Talazoparib is a potent and specific inhibitor of PARP 1 and 2(i) that is being developed by Medivation for the treatment of selected solid tumors. In pre-clinical studies, talazoparib has shown single-agent anti-tumor activity, as well as synergy in combination with lowered doses of DNA-damaging agents, due to its dual mechanisms of cytotoxicity, PARP trapping, and inhibition of PARP enzyme activity. Trapping of PARP on DNA impairs DNA replication resulting in tumor cell death. Talazoparib currently is in Phase III development for patients with locally advanced and/or metastatic breast cancer who harbor a germline BRCA1/2 mutation.