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Posts Tagged ‘Genentech’


Proteins that control neurotransmitter release

Author & Curator: Larry H. Bernstein, MD, FCAP

Richard H. Scheller, PhD

The sec6/8 Complex Is Located at Neurite Outgrowth and Axonal Synapse-Assembly Domains

Christopher D. Hazuka, Davide L. Foletti, Shu-Chan Hsu, Yun Kee, F. Woodward Hopf, and Richard H. Scheller
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5428

The Journal of Neuroscience, February 15, 1999, 19(4):1324–1334   http://www.jneurosci.org/content/19/4/1324.full.pdf

The molecules that specify domains on the neuronal plasma membrane for the delivery and accumulation of vesicles during neurite outgrowth and synapse formation are unknown. We investigated the role of the sec6/8 complex, a set of proteins that specifies vesicle targeting sites in yeast and epithelial cells, in neuronal membrane trafficking. This complex was found in layers of developing rat brain undergoing synaptogenesis. In cultured hippocampal neurons, the sec6/8 complex was present in regions of ongoing membrane addition: the tips of growing neurites, filopodia, and growth cones. In young axons, the sec6/8 complex was also confined to periodic domains of the plasma membrane. The distribution of synaptotagmin, synapsin1, sec6, and FM1–43 labeling in cultured neurons suggested that the plasma membrane localization of the sec6/8 complex preceded the arrival of synaptic markers and was downregulated in mature synapses. We propose that the sec6/8 complex specifies sites for targeting vesicles at domains of neurite outgrowth and potential active zones during synaptogenesis. Key words: synaptogenesis; neurotransmission; secretion; exocytosis; synaptic vesicle; vesicle targeting

Targeting of vesicles to synaptic sites during development may use similar mechanisms as those involved in vesicle fusion underlying membrane outgrowth. Before contact with a postsynaptic target, axons possess mobile vesicle clusters bearing synaptotagmin, which fuse with the plasma membrane after stimulation (Matteoli et al., 1992; Kraszewski et al., 1995; Dai and Peng, 1996). Thus, growing axons must contain the molecular machinery required for constitutive exocytosis, endocytosis, and activitydependent vesicle release. However, it is unclear how vesicles become clustered at synapses. Although vesicle fusion in axons might occur anywhere along the plasma membrane, there must be membrane targets that signal the clustering of vesicles for synapse formation. Furthermore, it is unclear how sites of vesicle exocytosis are modified as the neuron forms stable contacts with postsynaptic partners.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rytis Prekeris*, Jason M. Davies*, and Richard H. Scheller#
JBC Papers in Press. Published on July 31, 2001 as Manuscript M106133200
http://www.jbc.org/content/early/2001/07/31/jbc.M106133200.full.pdf

Rab11, a low molecular weight GTP binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the TGN. In this study we describe a novel Rab11 effector, EF hands containing Rab11 interacting protein (eferin). In addition, we identify a 20 amino acid domain that is present at the C-terminus of eferin and other Rab11/25 interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrate that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for the binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Members of the Rab/Ypt GTPase family have emerged as important regulators of vesicular trafficking (1). Rab proteins have been proposed to mediate a variety of functions, including vesicle translocation and docking at a specific fusion sites. Like all small GTPases, Rabs cycle between active (GTP bound) and inactive (GDP bound) conformations (2). In the GTP bound state, Rab proteins can bind a variety of downstream effector proteins, while GTP hydrolysis leads to a conformational change in the “switch” region that renders the Rab GTPase unrecognizable to its effector proteins (3,4). A key question in understanding the interactions between Rabs and their effectors concerns the mechanisms by which Rab GTPases specifically bind a diverse spectrum of effectors and how this is regulated by the common structural motif used as a GTP switch. Biochemical and genetic studies have identified several hypervariable regions that might be involved in determining Rab specificity, including N- and C-termini, as well as α3/β5 by guest on September 6, 2015 http://www.jbc.org/ Downloaded from loop (5,6). Indeed, the recently reported structure of Rab3a bound to a putative effector, rabphillin-3a, revealed that Rab3a/rabphillin-3a complex interacts through two main regions (7). The first consists of conformationally sensitive “switch” regions of Rab3a bound to the a1 helix and the C-terminal part of rabphillin-3a. The second involves the SGAWFF domain of rabphillin-3a which fits into a pocket formed by the three hypervariable complementary determining regions (CDRs) of Rab3a, corresponding to the N- and C-termini and α3/β5 loop. Thus, it appears that the hypervariable RabCDR are involved in determining the specificity of effector binding, while the conserved “switch” regions impart GTP dependency and binding. It remains to be determined, however, whether this paradigm also applies to other Rab/effector complexes. Rab11a, -11b, and -25 are closely related members of Rab GTPase family that have been implicated in regulating a variety of different post-Golgi trafficking pathways, such as protein recycling (8), phagocytosis (9), insulin-stimulated Glut4 insertion in the plasma membrane (10), and membrane trafficking from early endosomes to the transGolgi network (11). During the last few years several Rab11/25 interacting proteins have been identified, including Rab11BP/Rabphilin-11, Rip11, nRip11, and myosin Vb (12- 15). However, the mechanisms of their function, as well as molecular aspects of their interactions with Rab11, remain to be fully understood. In the present study, we report the identification of EF-hands containing Rab11/25 interacting protein (eferin). Furthermore, we characterized a Rab binding domain (RBD11) which is present at the Cterminus of eferin as well as other Rab11/25 binding proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrated that RBD11 is the region which encodes the specificity for Rab11/25, but is distinct from the region interacting with Rab “switch” domain, since its interactions with the Rab11/25 are not GTP-dependent.

The functional significance of the differences in Rip and eferin interactions with Rab11/25 remains to be determined. One possibility is that additional cellular factors can regulate the affinity of Rab11/25 binding to its effectors. Indeed, the recombinant full length Rip11 binds poorly to Rab11a in pull down and yeast-two hybrid assays as compared to full length endogenous Rip11 from cellular TX-100 extracts (data not shown). Furthermore, it has been previously shown that Rip11 can also interact with γSNAP and cytoskeleton (13,24). Thus, the interactions of Rips and eferin with different factors could be used as a means of differentially regulating Rab11/25 binding. Alternatively, the Rab11/25 binding motif in eferin and Rip11 might be conformationlly hidden and require activation before binding to Rab11/25. We have previously demonstrated that phosphorylation of Rip11 plays an important role in its trafficking (13). Thus, differential phosphorylation on Rab11/25 binding motifs could also play a role in regulating the binding of Rip11 and eferin to Rab GTPases. Despite to recent progress in understanding the roles of Rabs and their effectors in regulating membrane trafficking, we are only beginning to unravel the structural determinants of their function. Identification and characterization of the Rab11/25 binding regions in Rip and Eferin proteins will be of a crucial importance in understanding the molecular mechanisms involved in differential regulation of the variety of Rab11-dependent trafficking pathways.

J. Immunol. Methods
J Immunol Methods 2008 Mar 14;332(1-2):41-52. Epub 2008 Jan 14.
Genentech Inc., 1DNA Way, South San Francisco, California, 94080, United States. jagath@gene.com
Cysteines with reactive thiol groups are attractive tools for site-specific labeling of proteins. Engineering a reactive cysteine residue into proteins with multiple disulfide bonds is often a challenging task as it may interfere with structural and functional properties of the protein. Here we developed a phage display-based biochemical assay, PHESELECTOR (Phage ELISA for Selection of Reactive Thiols) to rapidly screen reactive thiol groups on antibody fragments without interfering with their antigen binding, using trastuzumab-Fab (hu4D5Fab) as a model system

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding.

Neuron
Neuron 2008 Nov;60(3):400-1

Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.

Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet-Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly.

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione.

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood.

Nat. Med.
Nat Med 2013 Oct;19(10):1232-5
Genentech Research and Early Development, 1 DNA Way, San Francisco, California, USA.
MAbs
MAbs 2014 Jan-Feb;6(1):95-107
Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry.

Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated.

Richard H Scheller, PhD

Published on 16 Sep 2014

The Keck School of Medicine of USC is the first medical school in the nation to host the Lasker Lectures, featuring recipients of the prestigious 2013 Albert Lasker Basic Medical Research Award. In this installment, Richard H. Scheller, PhD, executive vice president of Genentech research and early development, discusses breakthoughs in drug development that are turning the tide in the war against cancer.

https://www.youtube.com/watch?v=Fx54EVJMcxM

Kavli Prize 2015

Xenon Pharmaceuticals Appoints Dr. Richard H. Scheller to Its Board of Directors

Biopharmaceutical company Xenon Pharmaceuticals (NasdaqGM:XENE) reported on Monday the addition of Richard H. Scheller, PhD to its board of directors.

Most recently, Dr Scheller has served as chief science officer and head of Therapeutics at 23andMe.

Previously Dr Scheller was the executive vice president at Genentech Research and Early Development & a member of the Roche Corporate Executive Committee; chief scientific officer, executive vice president of Research and senior vice president of Research at Genentech; as well as a professor of Molecular and Cellular Physiology and of Biological Sciences at Stanford University Medical Center and an investigator of the Howard Hughes Medical Institute.

Dr Scheller is currently an adjunct professor in the Department of Biochemistry and Biophysics, School of Medicine at the University of California, San Francisco.

He has been a Director at Xenon Pharmaceuticals Inc. since March 16, 2015 and Medrio, Inc. since November 2012. He serves as a Member of the Medical and Scientific Review Board of Evotec (US), Inc. (Renovis Inc.). In 2014, he was named a trustee of Caltech. He served as a Member of Scientific Advisory Board of Intra-Cellular Therapies, Inc. and Rinat Neuroscience Corporation.

He served on numerous advisory boards including the National Advisory Mental Health Council of the National Institutes of Health. Dr. Scheller served as chairman of the Genentech Foundation’s board of directors. He is a globally recognized leader in biomedical research.

He has published over 200 papers in scientific journals, and worked in cell biology. He has received several additional awards for his work elucidating the molecular mechanisms governing neurotransmitter release, including the 2013 Albert Lasker Basic Medical Research Award, the 2014 California Institute of Technology’s Caltech Distinguished Alumni Award, the 2010 Kavli Prize in Neuroscience, and the 1997 U.S. National Academy of Sciences Award in Molecular Biology. He is a Fellow of the American Academy of Arts and Sciences. Dr. Scheller holds a Doctorate in Chemistry from the California Institute of Technology in 1980, where he was also a Postdoctoral Fellow, Division of Biology. He was also a Postdoctoral Fellow at Columbia University, College of Physicians & Surgeons. He has Bachelor’s Degree in Biochemistry in 1975 at the University of Wisconsin, Madison.

Education: 1971-1975 University of Wisconsin-Madison B.S. – Biochemistry with Honors 1975-1980 California Institute of Technology Ph.D. – Chemistry – Advisor: Eric H. Davidson 1980-1981 California Institute of Technology Postdoctoral Fellow-Division of Biology Advisor: Eric H. Davidson 1981-1982 Columbia University-College of Physicians & Surgeons Postdoctoral Fellow-Molecular Neurobiology Advisors: Richard Axel and Eric R. Kandel Industry Positions: 2001-2003 Senior Vice President – Research Genentech, Inc. 2003-2009 Executive Vice President – Research Genentech, Inc. 2008-2009 Chief Scientific Officer and Executive Vice President – Research Genentech, Inc. 2009- Executive Vice President – Genentech Research and Early Development (gRED) and Member of the Enlarged Roche Corporate Executive Committee Academic Appointments: 1982-1987 Assistant Professor, Department of Biological Sciences, Stanford University 1987-1990 Associate Professor, Department of Biological Sciences, Stanford University 1990-1993 Associate Professor, Department of Molecular and Cellular Physiology, Stanford University Associate Professor (by courtesy), Department of Biological Sciences, Stanford University

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Reporter: Aviva Lev-Ari, PhD, RN

 

Kinase Inhibitors

Seventh Annual

Novel Strategies for Kinase Inhibitors

Exploring New Therapeutic Areas

September 24-25, 2013  | Boston, MA

Dr. Jeffrey Settleman, Senior Director of Discovery Oncology at Genentech, to Present “The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors” at Novel Strategies for Kinase Inhibitors Conference

The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors

Selective kinase inhibitors have been clinically validated as an important class of oncology drugs. While mutational activation of the targeted pathway largely defines the patient population most likely to benefit from treatment, there is considerable variability among patients with respect to the magnitude and duration of benefit, implicating intrinsic resistance mechanisms. We find evidence of a potentially broad role for stromally-produced growth factors in clinical response to kinase inhibition. > Read More in NatureDr. Settleman’s research is focused on cancer cell biology and therapeutics. He is particularly interested in personalized cancer medicine and mechanisms of drug resistance. Since 2010, Dr. Settleman has been at Genentech, where he is currently the Senior Director of Discovery Oncology, overseeing efforts to identify and validate targets for oncology drug discovery and to discover predictive biomarkers for new cancer therapies. Before Genentech, Dr. Settleman was Director of the Center for Molecular Therapeutics and the Scientific Director of the Massachusetts General Hospital Cancer Center. He joined the Harvard School of Medicine faculty in 1992 and was named the Laurel Schwartz Professor of Oncology at Harvard Medical School in 2008. Dr. Settleman completed his postdoctoral fellowship at the Whitehead Institute for Biomedical Research at M.I.T. in Dr. Robert Weinberg’s laboratory. He earned his Ph.D. in genetics from Yale University in 1989.

 

Learn More   |   View Brochure   |   Register  (Deadline to Save Up to $250 is August 16)

Recommended Short Courses*

– New Class of Kinase Inhibitors: Covalent Modifiers

– Advancing Tools & Technologies for Fragment-Based Design

* separate registration required for short courses

Conference-at-a-Glance

Beyond Cancer

Second Generation Janus Kinase Inhibitors

Jordan S. Fridman, Ph.D., Senior Director, Pharmacology, Incyte Corp.

BTK Inhibitors in Inflammation and Autoimmunity

John Douhan III, Ph.D., Senior Principal Scientist, Immunoscience, Pfizer

ARRY-382, a Selective cFMS Inhibitor for the Treatment of Osteolytic Bone Diseases

Dale Wright, Ph.D., Research Investigator, Senior Project Leader, Pharmacology, Array BioPharma, Inc.

Targeting B-Cell Receptor Signaling with PI3Kdelta Inhibitors for Treatment of Inflammatory Diseases and B-cell Malignancies

Kamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.

> Sponsored presentation (opportunities available)

Deregulated Cdk5-Targeted Inhibitor for Neuro-inflammation

Harish C. Pant, Ph.D., Chief; Laboratory of Cytoskeleton Protein Regulation, National Institute of Neurological Disease and Stroke/NIH

Orally Available, CNS Penetrant MLK Inhibitors for Treatment of Neurodegenerative Diseases

Val Goodfellow, Ph.D., CEO, Califia Bio, Inc.

Allosteric Kinase Inhibitors

JNK Inhibitor Discovery at Celgene – Tanzisertib and Beyond

Yoshitaka Satoh, Ph.D., Senior Principal Scientist, Medicinal Chemistry, Celgene

Highly Selective Allosteric FMS Kinase Inhibitors

Bryan Smith, Ph.D., Director, Biology, Deciphera Pharmaceuticals LLC

P529, An Allosteric Modifier of the TORC1 and TORC2 Complexes of the PI3K/Akt/mTOR Pathway

David Sherris, Ph.D., President and CEO, Paloma Pharmaceuticals, Inc.

Allosterically Targeting Polo-Like Kinase 1 for Selective Cancer Cell Killing

Kyung Lee, Ph.D., Senior Investigator, Section Head, Laboratory of Metabolism, National Cancer Institute

Interactive Breakout Discussion Groups

In a Class By Themselves: Discovery and Characterization of Allosteric  Modulators of Protein Kinases

Moderator: John Watson, Ph.D., Senior Research Investigator, Bristol-Myers Squibb, Lead Discovery, Evaluation, Profiling and Compound Management

Challenges Working with Non-competitive Kinase Inhibitors

Moderator: John Robinson, Ph.D., Senior Scientist, Medicinal Chemistry, Array BioPharma, Inc.

Repurposing Kinase Inhibitors

Moderator: Jordan S. Fridman, Ph.D., Senior Director, Pharmacology, Incyte Corp.

Overcoming Cancer Drug Resistance and Selective Kinase Inhibitors

++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Featured Speaker: The Role of Growth Factors in Resistance to Anti-Cancer Kinase Inhibitors

Jeffrey Settleman, Ph.D., Senior Director, Discovery Oncology, Genentech

++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Featured Speaker: Stromal Factors that are Targets for Pi-3 Kinase Inhibitor Therapeutics in the Control of Metastasis

Donald Durden, M.D., Ph.D., Professor, Department of Pediatrics; Director Pediatric Oncology Research, University of California, San Diego and CEO, SignalRx Pharmaceuticals

mTOR Inhibitor Torin-1 for Effective Targeting of Resistant Human Colon Cancer Stem Cells

Maria Giovanna Francipane, Ph.D., Post Doctoral Research Scholar, Pathology, University of Pittsburgh

Development of c-MET Kinase Inhibitors for Cancer Therapy and Drug Resistance

Xiangdong Liu, Ph.D., Drug Discovery Group, Incyte Corporation

Exploiting a Serendipitous Binding Opportunity in the Development of Highly Selective Rho Kinase Inhibitors

Erick Young, Ph.D., Distinguished Research Fellow, Medicinal Chemistry and Research Administration, Boehringer Ingelheim Pharma

PLENARY KEYNOTE PRESENTATIONS

Towards a Patient-Based Drug Discovery

Stuart L. Schreiber, Ph.D., Director, Chemical Biology and Founding Member, Broad Institute of Harvard and MIT; Howard Hughes Medical Institute Investigator; Morris Loeb Professor of Chemistry and Chemical Biology, Harvard University

Enteroendocrine Drug Discovery for Treatment of Metabolic Diseases

Paul L. Feldman, Ph.D., Senior Vice President, GlaxoSmithKline

> For sponsorship & exhibit information, including sponsored podium presentations, please contact Jon Stroup at 781-972-5483.

> Stay on and Attend Cardio-Metabolic Drug Targets

 

——————————————————————————————————————————————–

Novel Strategies for Kinase Inhibitors is part of Discovery on Target, the preeminent event on novel drug targets, which features more than 600 attendees, 150 scientific presentations, 12 conferences, and 10 short courses.

————————

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

CANCER BIOTHERAPEUTICS

ADCs, Multi-Specifics, Combined Therapies and Immunotherapy

Inaugural

TUESDAY , 5 NOVE MBER

»»PRE-CONFERENCE PLENARY SESION

16:55 Designing Receptor Binding Proteins with Highly Potent

Biological Function

Andreas Plückthun, Ph.D., Director and Professor, Biochemistry, University

of Zurich

Non-IgG molecules, unless armed with toxins or other effector units, are

usually thought to be limited in the biological responses they can elicit.

However, Designed Ankyrin Repeat Proteins (DARPins) are particularly

versatile, because of their favorable biophysical properties, and they can be

engineered into many formats. Using DARPins generated against members

of the EGFR family, and a combination of x-ray crystallography, signaling

studies, and in vivo experiments, it will be demonstrated how molecules

could be engineered to selectively induce apoptosis in tumors, and their

mechanism of action has been deduced. New intracellular sensors will be

described for such studies.

17:45 Immunotherapy with BiTE® Antibodies

Luis Borges, Ph.D., Scientific Director, Therapeutic Innovation Unit, Amgen, Inc.

BiTE® antibodies are potent bispecific single-chain antibodies that redirect T

cells to kill tumors. They engage a tumor target and a constant region of the

T cell receptor to recruit and activate polyclonal T cells to eliminate tumors.

They have demonstrated potent efficacy in various preclinical tumor models

and have now transitioned to clinical studies. Blinatumomab, a CD19xCD3

BiTE® antibody, is in clinical development and has shown high single-agent

response rates in patients with refractory or relapsed B-ALL and B-NHL.

18:30 End of Day

Wednesday, 6 November

07:45 Registration and Morning Coffee

08:30 Chairperson’s Opening Remarks

Jason Baum, Ph.D., Principal Scientist, Research, Merrimack Pharmaceuticals, Inc.

MULTI-SPECIFIC ANTIBODY PRODUCTS

08:35 Two-in-One Antibody Targeting EGFR and HER3 and Platform

Update

Germaine Fuh, Ph.D., Senior Scientist, Antibody Engineering, Genentech, Inc.

Mutation at the antigen binding sites of a mono-specific antibody may recruit a

second binding specificity such that each Fab arm exhibits dual binding function and

IgG with this dual action Fab (DAF) can be produced as conventional IgG. Proofof-

concept is a HER2/VEGF Two-in-One antibody; EGFR/HER3 Two-in-One DAF

antibody is in clinical phase II trial for treating epithelial cancer. The talk will cover the

generation and development of the EGFR/HER3 DAF antibody including preclinical

and clinical phase I data.

09:05 MM-141, a Bispecific Antibody Co-Targeting IGF-1R and Erbb3,

Overcomes Network Adaptation by Blocking Redundant Survival

Pathways

Jason Baum, Ph.D., Principal Scientist, Research, Merrimack Pharmaceuticals, Inc.

An integrated Network Biology approach was used to design and optimize MM-

141 to overcome limitations of first generation IGF-1R therapies by also blocking

heregulin-mediated compensation through ErbB3. MM-141 potentiates the activity

of both targeted therapies and chemotherapies through the combined inhibition

of PI3K/Akt/mTOR signaling as well as control over feedback loops triggered by

these agents.

09:35 Bispecific κλ-bodies for Selective Inhibition of CD47 in Cancer Cells

Nicolas Fischer, Ph.D., Head, Research, Novimmune SA

We have used our κλ-body platform to generate CD47-neutralizing bispecific

antibodies. These fully human antibodies are composed of a CD47-specific arm

and a targeting arm, specific to a tumor associated antigen (TAA). The preferential

neutralization of CD47 on TAA-expressing cancer cells should therefore show better

pharmacological properties and a broader therapeutic window as compared to nontargeted

anti-CD47 monoclonal antibodies. The presentation will also highlight how

light chain diversity can be exploited to create bispecific antibodies with favorable

manufacturability and stability profiles that facilitate their development path.

10:05 Sponsored Presentation (Opportunity Available)

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:05 Targeting Tumor Microenvironmental Signals with Bispecific

Antibodies

Alessandro Angelini, Ph.D., David H. Koch Institute for Integrative Cancer Research,

Massachusetts Institute of Technology (MIT)

We have developed bispecific antibodies that locally contravene soluble signaling

factors that establish the supporting tumor microenvironment that enables tumor

survival and growth. Soluble factors such as VEGF, TGF-β, and IL-8 play a demonstrated

role in tumorigenesis, and enhanced interdiction of these signals within the tumor

should enhance the therapeutic index of cancer therapy.

11:35 Novel Multi-Targeting Antibody Mixtures: Mode of Action and

Advantages Over Other Approaches

Michael Kragh, Ph.D., Director, Antibody Pharmacology, Symphogen A/S

This talk will present the selection of antibodies against tumor-related antigens to

obtain synergistic combinations, the benefits of simultaneous targeting of multiple

receptors, and examine pan-HER (EGFR, HER2 and HER3) targeting to address

tumor heterogeneity and plasticity.

12:05 Sponsored Presentation (Opportunity Available)

12:35 Luncheon Presentations (Sponsorship Opportunities Available) or

Lunch on Your Own

ADVANCES WITH CANCER IMMUNOTHERAPY

14:00 Chairperson’s Remarks

Andrea van Elsas, CSO, BioNovion B.V.

14:05 Cancer Immunotherapy Using Immune Modulating Antibodies

Andrea van Elsas, CSO, BioNovion B.V.

Immune rejection of human cancer has been an elusive goal until recently. T cell

modulating antibodies targeting CTLA-4 and the PD-1 pathway induced clinically

meaningful responses and long-term benefit in patients with metastatic cancer.

Successful immune rejection can come with significant immune related adverse

events. Immune oncology agents do not directly tumor cells but treat the patient’s

immune cells. In this presentation, the discovery of immune modulating antibodies

and their translation into clinical success will be discussed.

14:35 Immunocytokines: A Novel Potent Class of Armed Antibody

Laura Gualandi, Ph.D., Philochem A.G.

Antibodies are effective tools that can deliver molecules with potent therapeutic

activity, such as Cytokines, to the tumor site, minimizing toxic effects. Aspects like

molecular format, valence and the chosen target antigen contribute to the efficacy of

the immunocytokines in vivo. Combinatory therapeutic strategies with other agents

have also been recently investigated. This talk will cover advanced preclinical and

clinical data on armed antibodies discovered and developed by the Philogen group.

15:05 NKTT320: A Humanized Monoclonal Antibody for Cancer

Immunotherapy

Robert Mashal, CEO, NKT Therapeutics

Activation of iNKT cells has been shown to have therapeutic effects both in

PEGSummitEurope.com 7

6-7 November 2013

preclinical models and in patients with cancer, and represents an important pathway

for the immunotherapy of cancer. iNKT cells have an invariant T cell receptor (iTCR).

NKT Therapeutics is developing NKTT320, a humanized monoclonal antibody which

specifically recognizes the iTCR present exclusively on iNKT cells, and has been

shown to activate iNKT cells both in vitro and in vivo.

15:35 Refreshment Break in the Exhibit Hall with Poster Viewing

16:15 Novel Tumor-Targeted, Engineered IL-2 Variant (IL-2v)-Based

Immunocytokines for Immunotherapy of Cancer

Ekkehard Moessner, Ph.D., Group Leader, Protein Engineering, pRED, Roche Glycart A.G.

A novel class of immunocytokines will be discussed that are based on Fc containing

and also on non-Fc containing building blocks. The IL2 component is optimized for

improved performance in tumor targeting. Enhancement of in vivo efficacy, when

combined with ADCC competent antibodies, will be discussed.

ANTIBODY-DRUG CONJUGATES AND PAYLOADS

16:45 Next-Generation ADCs: Enabling Higher Drug Loading,

Alternative Payloads, and Alternative Targeting Moieties

Timothy B. Lowinger, Ph.D., CSO, Mersana Therapeutics, Inc.

The application of polymers to antibody-drug conjugate (ADC) design can provide

numerous advantages, including significantly higher capacity for drug payload;

utilization of alternative payloads not suitable for direct conjugation; improvement of

physicochemical properties; and utilization of protein recognition scaffolds beyond

the commonly used IgGs. Examples of these benefits achieved using Mersana’s

polyacetal-based conjugation system to create next-generation ADCs

will be presented.

17:15 Problem Solving Roundtable Discussions

Table 1: Engineering of Bispecific Antibodies

Moderator: Nicolas Fischer, Ph.D., Head, Research, Novimmune SA

Table 2: Antibody-Drug Conjugates: Linkers and Payloads

Moderators: Robert Lutz, Ph.D., Vice President, Translational Research &

Development, ImmunoGen, Inc.

Timothy B. Lowinger, Ph.D., CSO, Mersana Therapeutics, Inc.

Table 3: Site-Specific Conjugation of ADCs

Moderator: Pavel Strop, Ph.D., Associate Research Fellow, Protein

Engineering, Rinat-Pfizer, Inc.

Table 4: Cancer Immunotherapy: Reaping the Benefits

Moderators: Andrea van Elsas, CSO, BioNovion B.V

Luis Borges, Ph.D., Scientific Director, Amgen, Inc.

Table 5: Cancer Biotherapeutics in the Clinic

Moderators: Jason Baum, Ph.D., Principal Scientist, Research, Merrimack

Pharmaceuticals, Inc.

Martine Piccart, M.D., Ph.D., Head, Medical Oncology, Jules Bordet

Institute; Chair, ESMO (European Society for Medical Oncology)

18:15 Networking Reception in the Exhibit Hall with Poster Viewing

19:15 End of Day One

Thursday, 7 November

07:45 Breakfast Presentation (Sponsorship Opportunity Available) or

Morning Coffee

08:30 Chairperson’s Remarks

Robert Lutz, Ph.D., Vice President, Translational Research & Development,

ImmunoGen, Inc.

08:35 A Universal Chemically Driven Approach for Constructing

Homogeneous ADCs

David Jackson, Ph.D., Principle Scientist, ADC Discovery, Igenica, Inc.

Current ADCs in clinical development are heterogeneous mixtures that differ in

both DAR (drugs/antibody) and their conjugation sites. Igenica has invented novel

site-specific linkers to enable the synthesis of homogeneous ADCs. The linkers

are compatible with a variety of drug payloads and can be applied to any antibody.

Homogeneous ADCs were synthesized using the novel linkers and compared to

heterogeneous ADCs made with conventional linkers. Analytical data and activity of

the ADCs in tumor models will be presented.

09:05 Location Matters: Site of Conjugation Modulates Stability and

Pharmacokinetics of Antibody-Drug Conjugates

Pavel Strop, Ph.D., Associate Research Fellow, Protein Engineering, Rinat- Pfizer, Inc.

To understand the role of conjugation site, we developed an enzymatic method for

site-specific antibody-drug conjugation. This allowed us to attach diverse compounds

at multiple positions and investigate how the site influences stability, toxicity, and

efficacy. We show that the conjugation site has significant impact on ADC stability

and pharmacokinetics in a species-dependent manner. With this method, it is

possible to produce homogeneous ADCs and tune their properties to maximize the

therapeutic window.

09:35 Development of Second Generation Duocarmycin ADCs with

Superior Therapeutic Window

Marion Blomenröhr, Ph.D., Program Manager Biopharmaceuticals, Synthon

Biopharmaceuticals

The first generation ADCs have successfully exploited the mAb-driven tumor cell

targeting for optimization of efficacy, but have failed to reduce off-target toxicities.

This presentation will highlight Synthon’s second generation Linker-Drug technology

and its complementarity with novel proprietary duocarmycin payloads yielding highly

stable and potent ADCs, with an improved in vivo therapeutic window.

10:05 Producing Better Antibody-Drug Conjugates Sponsored by

(ADCs) Using ThioBridge™ Conjugation

Antony Godwin, Ph.D., Director, Science & Technology, PolyTherics Ltd

Next-generation antibody-drug conjugates will be required to be less heterogeneous

and have better stability. PolyTherics has developed ThioBridge™ for improved

conjugation of a cytotoxic payload at the disulfides bonds of antibodies, antibody

fragments and other targeting proteins. With ThioBridge™, the resulting ADC

has the benefit of reduced heterogeneity, as the drug to antibody ratio is limited

to a maximum of 4 with little DAR 0 species. Stability is also enhanced, as unlike

single thiol conjugation approaches at disulfides, ThioBridge™ is not prone to

drug deconjugation reactions in serum. In vitro and in vivo data for mAb and Fab

conjugates with an established payload confirms specific binding and activity.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

»»PLENARY SESION

11:05 Medical Treatment of HER2 Positive Breast Cancer: Two

Decades of a Fascinating History and More to Come

Martine Piccart, M.D., Ph.D., Head, Medical Oncology, Jules Bordet

Institute; Chair, ESMO (European Society for Medical Oncology)

The talk will cover multiple aspects of anti-HER2 treatment in breast cancer.

It will present a summary of the clinical results obtained with trastuzumab

and several other anti-HER2 drugs in breast cancer (lapatinib, TDM1,

pertuzumab). Issues like the treatment duration, biomarkers of resistance

to treatment will be debated. Finally it will discuss future promising

research strategies: neoadjuvant trials, comparison between anti-HER2

agents, combinations of these drugs and functional imaging.

11:50 Antibody-Drug Conjugates: From Bench to Bedside and Back

Robert Lutz, Ph.D., Vice President, Translational Research & Development,

ImmunoGen, Inc.

Antibody-drug conjugates are emerging as an exciting approach to the

development of antibody-based therapeutics. The growing preclinical and

clinical experience with maytansinoid conjugates such as Kadcyla (T-DM1) is

leading to an enhanced understanding regarding critical attributes for target

antigens, antibodies, payloads and linkers. The translational knowledge

is being incorporated into research and development efforts for the next

generation of ADC candidates.

12:35 End of Cancer Biotherapeutics

http://www.pegsummiteurope.com/PEGS_Europe_Content.aspx?id=123176&libID=123124

 

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Treatment for Metastatic HER2 Breast Cancer

Reporter: Larry H Bernstein, MD, FCAP
Leaders in Pharmaceutical Innovation
https://pharmaceuticalintelligence.com/2013/03/03/9680/Treatment for Metastatic HER2 Breast Cancer 

FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)
T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.
T-DM1 is indicated for patients who were previously treated with

  • the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the

  • HER2-targeted antibody trastuzumab
  • is chemically linked to the cytotoxin mertansine (DM1).

The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.  According to Richard Pazdur, MD, at the FDA Center for Drug Evaluation and Research, T-DM1 carries the drug-conjugate

  • directly to the cancer site
  • to shrink the tumor,
  • slow disease progression, and
  • prolong survival .

It is the fourth drug approved that targets the HER2 protein. Apart from lapatinib, which is marketed by GlaxoSmithKline, all the other HER2-targeted products have been developed and are marketed by Genentech/Roche. For T-DM1, the proprietary technology involved in the DM1 portion of the product was developed by ImmunoGen, working in collaboration with Genentech/Roche.

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of

  • lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months).

There were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy

  • 43.1% vs. 59.2%)

The approval represents a “momentous” day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

  • HER2-positive patients with metastatic disease have a therapy that offers prolonged disease control with less toxicity

 T-DM1 was more effective in EMILIA than standard therapy on every outcome:

  • overall response rate,
  • disease-free survival,
  • progression-free survival, and
  • overall survival.
Herceptin Fab (antibody) - light and heavy chains

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Ribbon diagram of the Fab fragment of , a , bo...

Ribbon diagram of the Fab fragment of , a , bound to the extracellular domain of HER2. Created using Accelrys DS Visualizer Pro 1.6 and . ; Legend Trastuzumab Fab fragment, Trastuzumab Fab fragment, HER2, extracellular domain (Photo credit: Wikipedia)

Breast cancer (Infiltrating ductal carcinoma o...

Breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody. (Photo credit: Wikipedia)

English: Breast cancer incidence by age in wom...

English: Breast cancer incidence by age in women in the United Kingdom 2006-2008. Reference: Excel chart for Figure 1.1: Breast Cancer (C50), Average Number of New Cases per Year and Age-Specific Incidence Rates, UK, 2006-2008 at Breast cancer – UK incidence statistics at Cancer Research UK. Section updated 18/07/11. (Photo credit: Wikipedia)

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Non-small Cell Lung Cancer drugs – where does the Future lie?

In focus: Tarceva, Avastin and Dacomitinib

 

UPDATED on July 5, 2013

(from reports published in New England Journal of Medicine on drug, crizotinib)

 

Curator: Ritu Saxena, Ph.D.

 

Introduction

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.

There are three common forms of NSCLC:

  • Adenocarcinomas are often found in an outer area of the lung.
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.

Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.

Treatment

Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.

FDA approved drugs for NSCLC

Abitrexate (Methotrexate)
Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) 
Alimta (Pemetrexed Disodium)
Avastin (Bevacizumab)
Bevacizumab
Carboplatin
Cisplatin
Crizotinib
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gefitinib
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel
Paclitaxel Albumin-stabilized Nanoparticle Formulation
Paraplat (Carboplatin)
Paraplatin (Carboplatin)
Pemetrexed Disodium
Platinol (Cisplatin)
Platinol-AQ (Cisplatin)
Tarceva (Erlotinib Hydrochloride)
Taxol (Paclitaxel)
Xalkori (Crizotinib)

On the basis of target, the drugs have been classified as follows:

Image

NSCLC Drug Market Analysis

NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020

Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.   

However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.

In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.

Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.

Tarceva (Erlotinib)

Generic Name: Erlotinib, Brand Name: Tarceva

Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781

Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.

Tarceva has been approved for different cancers and several indications have been filed-

  • non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
  • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
  • non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
  • non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease

Sales of Tarceva 

May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.

In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.

It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.

According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Avastin (Bevacizumab)

Generic Name: Avastin, Brand Name: Bevacizumab

Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435

Mechanism of Action

Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.

Targets

Vascular endothelial growth factor (VEGF, VEGF-A, VEGFA)

Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.

Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their tar­gets.

Avastin has been approved for different cancers and several indications have been filed:

  • colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
  • colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
  • renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
  • glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
  • ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
  • ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer

SOURCE:

New medicine Oncology Knowledge Base

Sales of Avastin 

As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.

It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)

Dacomitinib: New promising drug for NSCLC

Generic Name: Dacomitinib

Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804

PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.

Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.

SOURCE:

New medicine Oncology Knowledge base

Dacomitinib bests Erlotinib in advanced NSCLC:  Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.

In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.

SOURCE:

Randomized Phase II Study of Dacomitinib Versus Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer

The results indicated indicated the following:

  • Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
  • Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.

Patients were divided into groups by tumor type and following results were obtained:

  • Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
  • Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
  • PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.

The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.

Although adverse side effects were uncommon in both the groups, certain side effects such as:

  • mouth sores,
  • nailbed infections, and
  • diarrhea

were more common and tended to be more severe with Dacomitinib as compared to Tarceva.

Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.

Current status of Dacomitinib

Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.

SOURCE:

New medicine Oncology Knowledge base

*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.

REFERENCES

Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinib is an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.

  • Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine.  A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).

However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)

Reference: 

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Reposrter: Aviva Lev-Ari, PhD, RN

Dear Members of Congress: Don’t Gut the NIH Budget

10/19/12

dgollaher

In 1973, research spearheaded by Herbert Boyer at the University of California San Francisco and Stanley Cohen at Stanford University led to the discovery of recombinant DNA technology and, in turn, genetic engineering. That basic scientific investigation, supported by funding from the National Institutes of Health (NIH), ultimately spawned an entire industry. What we now call biotechnology and a company we now call Genentech were the beginnings of a vast series of inventions that have advanced commerce and human health around the globe.

More recently, the mapping of the human genome, completed in 2003, is driving revolutionary advances in science. The Human Genome Project, also fueled by NIH funding, has created new private-sector technologies including gene sequencing, consumer genomics, and personalized medicine. A study by Battelle calculates that the Human Genome Project has helped drive $796 billion in economic activity and supported 310,000 jobs in 2010 alone.

Today, the continued vibrancy of the biomedical industry in California and nationwide depends on many things, including a predictable and consistent regulatory review process, sufficient and appropriate coverage and payment policies and intellectual property protections. But the industry would not exist without the essential investments in basic research the federal government makes through the NIH.

Unfortunately, now, automatic federal spending cutbacks known as sequestration threaten the future of research and development and our nation’s global competitiveness in the fields of drugs, medical device and diagnostics. While China and South Korea have committed to government funding increases of 10 percent year over year, U.S. federal funding for research and development during the past decade has stalled.

A $2.5 billion cut to the NIH budget next year, which is what the blunt instrument of sequestration requires, would result in 2,000 fewer funded research grants, according to the Congressional Budget Office. This would mean fewer research teams working on the cures and treatments of tomorrow, as well as canceled or postponed purchases from companies that manufacture research tools like flow cytometers, mass spectrometers and gene sequencers used by scientists in their labs. A recent study conducted by United for Medical Research estimates that NIH funding cuts under sequestration would lead to 33,000 fewer jobs nationwide — 5,000 in California alone — and an overall $4.5 billion decrease in economic activity.

California is the worldwide leader in biomedical investment, research and development, with more than 2,300 biomedical companies, along with public and private research institutions, advancing scientific knowledge and developing new diagnostics tools, treatments, and technologies addressing diseases and illnesses like cancer, diabetes, HIV/AIDS, chronic pain, and cardiovascular, respiratory and infectious diseases.

California’s life sciences industry is also an important engine of economic growth, employing nearly 268,000 workers statewide, paying more than $20 billion in annual wages and accounting for $18.6 billion in exports to markets around the world. Venture capital investment has been important, but private investment builds upon inventions that originate from federal research funded by the NIH and National Science Foundation, which totaled $4.5 billion in California last year. Together, industry, research universities and institutions, venture capital and the NIH comprise one of the most successful and important public-private partnerships in our country.

It is essential that Congress funds the kind of critical research needed to meet patient and public health needs of tomorrow.

We urge legislators in Washington to safeguard and sustain this essential public-private partnership that produces improved public health, economic growth and job creation.

David Gollaher, Ph.D., is president and chief executive officer of the California Healthcare Institute (CHI). Based in La Jolla, CHI is a non-profit public policy research organization representing more than 250 leading medical device, biotechnology, diagnostics and pharmaceutical companies and public and private academic biomedical research organizations.

Source:

http://www.xconomy.com/national/2012/10/19/dear-members-of-congress-dont-gut-the-nih-budget/

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