Waters J.D.,University of California at San Diego |
Sanchez C.,Center for Nervous System Repair |
Sahin A.,Center for Nervous System Repair |
Futalan D.,University of California at San Diego |
And 13 more authors.
Journal of Neuro-Oncology | Year: 2012
Glioblastomas are among the most aggressive human cancers, and prognosis remains poor despite presently available therapies. Angiogenesis is a hallmark of glioblastoma, and the resultant vascularity is associated with poor prognosis. The proteins that mediate angiogenesis, including vascular endothelial growth factor (VEGF) signaling proteins, have emerged as attractive targets for therapeutic development. Since VEGF receptor-2 (VEGFR-2) is thought to be the primary receptor mediating angiogenesis, direct inhibition of this receptor may produce an ideal therapeutic effect. In this context, we tested the therapeutic effect of CT322, a selective inhibitor of VEGFR-2. Using an intracranial murine xenograft model (U87-EGFRvIII-luciferase), we demonstrate that CT322 inhibited glioblastoma growth in vivo and prolonged survival. Of note, the anti-neoplastic effect of CT322 is augmented by the incorporation of temozolomide or temozolomide with radiation therapy. Immunohistochemical analysis of CT322 treated tumors revealed decreased CD31 staining, suggesting that the tumoricidal effect is mediated by inhibition of angiogenesis. These pre-clinical results provide the foundation to further understand long term response and tumor escape mechanisms to anti-angiogenic treatments on EGFR over-expressing glioblastomas. © 2012 Springer Science+Business Media, LLC.
Khan J.A.,Bristol Myers Squibb |
Camac D.M.,Bristol Myers Squibb |
Low S.,Adnexus |
Tebben A.J.,Bristol Myers Squibb |
And 17 more authors.
Journal of Molecular Biology | Year: 2015
The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain (10Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest. © 2015 Elsevier Ltd.
Koide S.,University of Chicago |
Koide A.,University of Chicago |
Methods in Enzymology | Year: 2012
We describe concepts and methods for generating a family of engineered target-binding proteins designed on the scaffold of the 10th human fibronectin type III domain ( 10Fn3), an extremely stable, single-domain protein with an immunoglobulin-like fold but lacking disulfide bonds. Large libraries of possible target-binding proteins can be constructed on the 10Fn3 scaffold by diversifying the sequence and length of its surface loops, which are structurally analogous to antibody complementarity-determining regions. Target-binding proteins with high affinity and specificity are selected from 10Fn3-based libraries using in vitro evolution technologies such as phage display, mRNA display, or yeast-surface display. 10Fn3-based target-binding proteins have binding properties comparable to those of antibodies, but they are smaller, simpler in architecture, and more user-friendly; as a consequence, these proteins are excellent building blocks for the construction of multidomain, multifunctional chains. The ease of engineering and robust properties of 10Fn3-based target-binding proteins have been validated by multiple independent academic and industrial groups. In addition to performing well as specific in vitro detection reagents and research tools, 10Fn3-based binding proteins are being developed as therapeutics, with the most advanced candidate currently in Phase II clinical trials. © 2012 Elsevier Inc. All rights reserved.
News Article | May 14, 2008
Earlier this week we reported that bi-coastal biotech Fate Therapeutics had named its new CEO, Paul Grayson. Today the company officially announced Grayson, as well as the appointment of John Mendlein as executive chairman. Mendlein was most recently CEO of Boston-based Adnexus Therapeutics, which was bought by Bristol-Myers Squibb last October for more than $505 million. Fate Therapeutics is backed chiefly by Polaris Venture Partners in Waltham, MA, and Arch Venture Partners in Seattle, WA. Gregory T. Huang is Xconomy's Deputy Editor, National IT Editor, and the Editor of Xconomy Boston. You can e-mail him at email@example.com. Follow @gthuang
News Article | October 31, 2013
Red (and Green) Flags To Look for With Biotech’s Buyside Investors As Warren Buffett once pointed out, companies get the investors they deserve. Observations by the oracle-from-Omaha are hard to dispute, but how does that translate into practice if you’re a biotech company going through the IPO process and trying to read the signs in a whole new landscape of investors known as “the buyside”? Many people blog about raising capital from VCs, but there seems to be much less about understanding and assessing public investors. What are the signals that an investor sends about who they are, both red and green flags? There are talented people who help with this (bankers, IR professionals, etc) but it’s the company that actually has the relationship with its investors and needs to understand who owns their stock. Luke Timmerman & David Sable each wrote recently on “red flags” for biotechs—warning signs that a company has hidden issues (and “green flags”, a nice additional piece from David. They were insightful. Perspectives from thoughtful people outside of companies help. But inevitably…it also made me think of some of my personal experiences at Avila Therapeutics as we talked to crossover and public investors and at Adnexus Therapeutics where we had filed our S-1 but were acquired before completing an IPO. I also checked with a few of my fellow CEOs and CFOs, to ask about their experiences as they began to engage with public market investors. Red flags (signs of caution, aka, this investor’s interests may not be aligned with the company’s interests) 1) The break-the-rules ask. The investor asks you to tell them non-public info. And when you politely decline, they either get irritated or just repeat the question over and over (and over). While most of the red flag experiences are relatively uncommon, this one isn’t. Nearly every CEO & CFO has this experience regularly. 2) No true interest. Investors who only meet to pump the company for information about the competitive landscape. Often this is because they have a big position (long or short) on someone else in the field. This person is 100 percent not interested in investing in your company (and, BTW, it’s obvious when someone thinks this). There are other ways for an investor to do their research. No one likes feeling used. 3) “Hi honey, who’s presenting?” and other forms of disrespectful behavior. Any comments or behavior that is patronizing, sexist, racist, homophobic, or otherwise disrespectful. Fortunately this is reasonably rare, and I think at least sometimes it’s more of a blind spot than intentional, but it’s non-zero and tends to emerge in work-social settings (the industry cocktail party and such). Many investors never behave this way, so for those who still make this mistake, they’re risking investment opportunities. A variant on this: I once had an investor say to me at our first meeting “I never trust management, all biotech CEOs lie.” Certainly trust must be earned, continually, but this was a red flag; what would it be like to have this person as an investor? 4) “I want to grill you on this 15-year old research paper”. This came up a few times as I surveyed my colleagues, and it’s primarily a question of focus. Biotech investors are generally very smart and well-informed, but sometimes they can delve a bit too much in the weeds or get stuck on minutia that may be dated or not really relevant to the programs at hand. Alternatively, when learning about new company, the junior analyst tasked to figure out the science can become overwhelmed. They’re under pressure to learn it so that they can explain it internally yet may lack the experience to know where to focus their efforts (hence questions on a 15-year old paper). Often this person doesn’t listen well, which is challenging because the company can actually provide the needed scientific roadmap. Tough, critical questions are always welcome; arbitrary or tangential ones aren’t a good use of time. 5) “I just want to help you be successful”. This is the sentiment from those investors who want to help the company design clinical trials or identify the best indications to pursue or basically tell the team how to manage the company. Good management teams value input and ideas, but it is their job to run the company. Justifying every decision to investors either means that the investor doesn’t trust management (in which case they probably shouldn’t invest) or that they really want to be in an operating company (in which case they should join an operating company). 6) Very short-term interests. There are likely many versions of this, but certain types of behavior telegraph that an investor’s interests are very short-term. For example, during an IPO, an investor only asks how the road show is going and what the interest level is. This is a flag that they may only be a flipper, not someone with long-term interests. Or when a discussion concentrates only on upcoming milestones to see whether it’s safe to short the stock. 1) Investors Who Prepare. There’s a reason this is #1. Green flags go up when an investor has read the S-1 and … Next Page »
News Article | August 1, 2013
New businesses today have it particularly easy when it comes to adopting cloud applications, as many Software-as-a-Service (SaaS) offerings can be deployed with just a few clicks of a button. But for companies with on-premises business applications that work for them and are not quite mobile friendly, virtualisation can lend a helping hand. Adnexus is a wireless communications field services and deployment company based in Sydney. A big part of the business is the installation of network elements in telecommunications networks. The company's staff work all across Australia, often flying in and out of location, and can stay at a site for days, weeks, or even months. Because of this, Adnexus has always had a disparate workforce, and three years ago, the company sought to serve its workers better when they're on the road. "By nature, we're a highly mobile workforce, but our business applications weren't fabulous for mobile," Adnexus commercial manager Renee Mathie told ZDNet. The applications were hosted in Adnexus' head office in Sydney in a server room. The company had a virtual private network (VPN) so that staff could get access to its primary systems remotely, but the lag time for accessing applications was excruciatingly long. "We weren't getting real-time reporting and visibility in the field," Mathie said. "We really wanted to take advantage of being able to work in real time, and to move our systems into something that was more available and faster." "We just wanted to work smarter, basically, and really drive a lot of process improvements." Adnexus got in touch with Conetix, a Parallels partner, to kick off a virtualisation project and begin its journey into the cloud. Initially, Adnexus was very eager to seek out and adopt new on-demand applications, but with legacy issues to consider, it was going to be a difficult task. "Because we wanted to get into cloud, we almost just started looking for new applications that would be on-demand," Mathie said. "But that's such a huge thing to put a business through, especially when you already have systems that work, but they're just not mobile or your infrastructure doesn't support that." "We came to the conclusion of 'well, maybe we don't have to turn off the systems that actually work for us, we just need to make them work for us better'." One of the challenges Adnexus had was the inability to back up its data. Because the company kept everything on its main server in Sydney, there were concerns about what would happen to all of its data in case of emergencies. "There were concerns around what would happen if there was a fire, a flood — or what if somebody came and just stole the server," Conetix owner Jamin Andrews told ZDNet. He worked closely with Adnexus on the project. The speed at which staff members were able to access business systems was also a challenge. "With a lot of disjointed systems, we looked at trying to solve some of those problems one at a time," Andrews said. "The first issue was simply on bringing some of Adnexus' systems locally into the cloud using our virtualisation services." This allowed Adnexus to get rid of a lot of its hardware, along with its IT department, as well. Conetix now deals with its IT needs. "We migrated the first stage of Adnexus' systems to our virtualisation servers," Andrews said. "From a business perspective, it was very seamless, with no downtime." While the process only took a day to complete, Andrews credited weeks of careful planning for the seamless transition. After three years, the project is still ongoing, but it's only in the last 12 months that Conetix has worked extremely closely with Adnexus. "Conetix is now looking after our project management information systems, knowledge management systems, and our business process operations," Mathie said. "It is also helping us with Atlassian's Confluence and other design tools relevant to our industry." Workers can now access all of the virtualised apps and business systems online through a central portal. Adnexus continues to work with Conetix to identify what other apps and services it can put into the cloud. "It's amazing — it feels like the way we used to work was ancient history," Mathie said. "I wonder how we ever did it back then, to be honest." The cost saving is also a huge bonus. According to Andrews, the cost savings in the early days worked out to be around 40 percent of what Adnexus would have spent if it continued to do its IT in-house. "As time goes on, when you look at cost savings, they don't require an in-house IT person, they don't have to worry about hardware refresh, or require any of that infrastructure technology," he said. "Adnexus gets the benefit of our cloud services when we upgrade, and it doesn't have to pay any more money at all." Most recently, Adnexus was upgraded to the Parallels Cloud Server (PCS) in the back end. This allowed the company to take advantages of the cloud storage offering with PCS. "Every site location Adnexus goes to, it takes a number of images; they're fairly large and have to be kept in raw formation," Andrews said. "Because it was keeping such large amounts of images, PCS was just a neat offering for them, and helped offset a lot of the large images onto multiple servers." "That's a huge advantage of virtualisation; it's the fact we can migrate Adnexus to bigger and better services if required."
News Article | January 11, 2012
The new Flagship Ventures Fund IV L.P. was set at $250 million, but investors exceeded that amount. Investors included all types of organizations from foundations to corporations to individuals, including a few new limited partners that had not contributed to previous funds. Flagship’s portfolio companies seem to be tackling big, human-scale problems from energy to epidemics, and the firm has seen exits that match that ambition. Some of its more notable exits include Adnexus Therapeutics, which was sold for $430 million to Bristol-Myers Squibb; Morphotek, which was acquired for $325 million by Japanese big pharma company Eisai; and Hypnion, which was bought by Lilly for an undisclosed sum. “We are quite pleased by the market’s reaction to our fourth fund,” said Flagship CEO and managing partner Noubar Afeyan in a release. “Despite the difficult environment for fundraising, especially for early-stage venture firms, we received strong support from our prior investors, as well as from several new important limited partners. We believe that the firm’s investment strategy and … history of building valuable, transformative companies are well aligned with the world’s ever increasing reliance on innovation, entrepreneurship and value creation.” Indeed, VC fundraising had a lackluster year in 2011, according to Dow Jones analysts. On average, a U.S.-based venture capital firm in 2011 was only able to raise around $120 million. Flagship’s last fund, which launched in pre-economic-meltdown 2007 with a healthy $235 million raise, fed a portfolio of 24 ventures such as Joule Unlimited, which aims to solve the global energy crisis with a biofuel alternative, and Selecta, which produces nanotechnology-powered vaccines. Counting the new fund, Flagship now manages more than $900 million of early-stage capital and has cultivated a portfolio of more than 65 companies. Also, 25 of those companies came from inside Flagship itself via the firm’s in-house venture creation group, VentureLabs. In addition to continuing its investment in early-stage companies, Flagship will use part of the new fund to invest in later-stage companies.
News Article | April 30, 2013
I was intrigued by the concept of an “innovation supply chain” for biotech raised in last week’s Xconomy discussion with Noubar Afeyan of Flagship Ventures. The basic idea is that if there’s agreement about certain experiments, results, and value with a pharma company, then a biotech company can focus on delivering those results, the pharma company would have greater assurance of a “supply” of new drug development candidates, and investors would be more assured that they would be rewarded for their investment. I found myself arguing with my computer screen as I read it. To be fair, there’s a broad spectrum of what constitutes a biotech company. Some companies are working on valuable but incremental improvements while others are attempting to develop broad new biologies or modalities. Noubar himself helps develop companies across that spectrum (e.g., Moderna Therapeutics and Syros Pharmaceuticals are two recent examples of Flagship portfolio companies pursuing very innovative science). (Disclosure: I’ve known Noubar a long time, and he was a founder, investor, and director of Adnexus Therapeutics, where I was head of business development. I think he is deeply creative and sees further down the road than most). These days there are lots of initiatives around single-asset entities, and you could argue that each of these fits into the supply chain concept that Noubar put forward: —CMEA’s Velocity Pharmaceutical Development (whose tagline is “we build drugs, not companies”) —NEA’s & Pfizer’s Cydan, which calls itself an “accelerator” and focuses on drugs for rare diseases. But if these initiatives are to deliver truly important new medicines, they need to bring more to the table than just an ability to execute on drug development plans outside of pharma companies’ profit-and-loss statements. Aligning Interests? Or teaching to the test? One of the concepts in the supply chain model described by Xconomy is that “innovators should be working closely with the acquirers from the early days, getting regular feedback…[this can] force the startup to run the key experiments needed to prove the value of their idea, rather than simply guessing what the pharma companies want to see.” Yes and no. Take it too far, and it’s like standardized testing in education and the concern that teachers “teach to the test.” This isn’t unique to an acquisition scenario; every business development meeting is an opportunity to get input. I think this is actually an advantage that small companies have—because we typically need to cultivate potential future partners and investors, we constantly put our data and plans up for external scrutiny. That’s a lot of opportunities to get feedback and new ideas. But you have to sort through that feedback carefully. Some … Next Page »
News Article | February 26, 2010
Avila Aims to Trump Vertex With Drug that Hits Hepatitis C Virus and Won’t Let Go Avila Therapeutics can’t be accused of thinking too small. This Waltham, MA-based startup is on a quest to show it has the scientific chops to build a better drug than one of Boston’s anchor biotech companies—Vertex Pharmaceuticals. So this is shaping up to be a big year for Avila (AH-vill-uh), as it plans to start clinical trials of a drug for hepatitis C, and another with potential for certain cancers and autoimmune diseases. The company raised $30 million last July, recruited an experienced biotech dealmaker as CEO, and has laid out some ambitious goals to put its money and people to work. For those new to the Avila story, it’s built on chemistry. The company is developing conventional small-molecule oral pills with a special feature. The Avila drugs form covalent bonds with their targets on cells. These bonds are supposed to completely, and irreversibly, shut down the biological activity of the intended protein target they hit on cells. That’s different from conventional therapies that connect with their targets via ionic or van der Waal bonds, which puts them in a state of “dynamic equilibrium” in which they are bouncing on and off the target, says CEO Katrine Bosley. Why does that matter? By completely shutting down the target, Avila thinks it has found a way to improve upon the trailblazing work of Vertex in hepatitis C, and it might be able to nail other targets pharma companies have long pursued, but couldn’t effectively block. “It’s getting the attention of pharma companies. Pharma companies are always looking for new innovation from beyond what they do within their four walls, and covalent drugs haven’t been much explored in the industry,” Bosley says. “As we develop a data set that says we can develop very specific covalent drugs, it’s intrigued a lot of people. Scientists are scientists. If you can get a new result that can’t be achieved another way, they want to talk about that.” I pressed Bosley for a bit more explanation of how its lead drug is differentiated from Vertex’s telaprevir. That drug, a protease inhibitor, has helped Vertex create an $8 billion stock market valuation, largely because clinical trials have shown it can basically double the traditional cure rates for patients with hepatitis C, while shortening the usual year-long treatment regimen by half. Analysts predict Vertex could exceed $2 billion in U.S. sales alone after a couple years on the market, and the worldwide potential is vast with an estimated 170 million people infected. Bosley didn’t want to sound dismissive of what Vertex has done. “Obviously everybody is excited about Vertex’s telaprevir, it’s a great drug, they’ve done a beautiful job advancing the molecule and developing the clinical paradigm in treating hepatitis C,” Bosley says. But Bosley clearly sees room for improvement, and Avila thinks it has found a way. One of the challenges with viruses is that they mutate, essentially switching … Next Page »