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.

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting.
This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660.
Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure.
Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.
Boehringer Ingelheim.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Erythropoiesis-stimulating agents (ESAs) are widely used for treating chronic kidney disease (CKD)-associated anemia. The biological activity of ESAs is mainly regulated by the number of sialic acid-containing carbohydrates on the erythropoietin (EPO) peptide. Sialidase, a sialic acid-metabolizing enzyme that accumulates in CKD patients, is suspected of contributing to shortening the circulation half-life of ESAs. Epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), is an EPO integrated with methoxypolyethylene glycol (PEG). It has been suggested that C.E.R.A. may exert a favorable therapeutic effect, even under conditions of elevated sialidase; however, no detailed investigation of the pharmacological profile of C.E.R.A. in the presence of sialidase has been reported. In the present study, we injected C.E.R.A. or EPO pre-incubated with sialidase into rats, and assessed the hematopoietic effect by reticulocyte count. The hematopoietic effect of C.E.R.A., but not EPO, was preserved after sialidase treatment, despite the removal of sialic acid. Proliferation of EPO-dependent leukemia cells (AS-E2) was significantly increased by desialylated C.E.R.A. and EPO compared to non-treated C.E.R.A. or EPO. In conclusion, we show that C.E.R.A. exerts a favorable hematopoietic effect even under conditions of elevated sialidase. Our findings may contribute to a better understanding of CKD and more effective therapeutic approaches based on a patient’s profile of anemia.

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Clinical trials with immune checkpoint inhibitors have provided important insights into the mode of action of anticancer immune therapies and potential mechanisms of immune escape. Development of the next wave of rational clinical combination strategies will require a deep understanding of the mechanisms by which combination partners influence the battle between the immune system’s capabilities to fight cancer and the immune-suppressive processes that promote tumor growth. This review focuses on our current understanding of tumor and circulating pharmacodynamic correlates of immune modulation and elaborates on lessons learned from human translational research with checkpoint inhibitors. Actionable tumor markers of immune activation including CD8(+)T cells, PD-L1 IHC as a pharmacodynamic marker of T-cell function, T-cell clonality, and challenges with conduct of trials that ask scientific questions from serial biopsies are addressed. Proposals for clinical trial design, as well as future applications of peripheral pharmacodynamic endpoints as potential surrogates of early clinical activity, are discussed. On the basis of emerging mechanisms of response and immune escape, we propose the concept of the tumor immunity continuum as a framework for developing rational combination strategies.Clin Cancer Res; 22(8); 1865-74. ©2016 AACR (Free AACR Whitepaper) SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "OPPORTUNITIES AND CHALLENGES IN CANCER IMMUNOTHERAPY".
©2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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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.