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bloodstream, by attaching to adhesion explored. Alpha d is highly expressed Innovations proteins made by vascular endothelial by , including the foamy cells, which line blood vessels. Once macrophages in atherosclerotic attached, the immune cells squeeze plaques. Although redux past the endothelial cells and seek remains a possible treatment target for out disease-causing microbes. the future, it will not be the subject of ICOS Corporation ICOS is attempting to block the the first Alpha d clinical trials. “Our attachment process with strategy is to identify applications Chemistry & Biology January 1999, LeukArrest™, a humanized with short endpoints,” says Gallatin. 6:R23–R24 against the immune cell integrin “For a medium-sized biotech we may © Current Biology Ltd ISSN 1074-5521 CD11/CD18. Although the therapy is not start with atherosclerosis.” directed at the immune system, the Companies cannot live on pedigree disease targets are not all autoimmune Large small molecules alone, but it doesn’t hurt to have a diseases. Instead, ICOS is using ICOS is initially attacking adhesion history of fine corporate decision- LeukArrest™ to minimize or prevent molecules with , but the making backing you up. For ICOS the damage that immune cells do to next line of drugs, based on a Corporation (Bothell, ) that tissues after an interruption in blood collaboration with Abbott means a co-founder and CEO, George flow. Phase II trials are underway for Laboratories (Abbott Park, Illinois), Rathmann, who has already directed a , heart attacks, hemorrhagic may be small molecules. The design start-up called Amgen to billion-dollar and . of these molecules will not be a sales, and a star-studded board of The LeukArrest™ antibody simple task. “Unlike , cell- directors that includes William H. recognizes all the variants of adhesion targets have broad points of Gates III of Microsoft fame. Gates is CD11/CD18, which are found on contact,” says Gallatin. “You need to also a major ICOS investor. different immune cell lineages, and build a bigger small molecule by The science is a mixture of the it therefore has the potential to be a piecing together small molecules.” Amgen model — proteins as drugs — profound immunosuppressant. That is just what Abbott’s SAR by and the more standard approach of “If you dose patients at high levels NMR (structure–activity relationships using small-molecule therapeutics. ad infinitum one could expect severe by nuclear magnetic resonance) “We thought we needed to do that to immunosuppression, but in the technique achieves (see Chem. Biol. 4, fully leverage the discoveries here, clinical setting that is not how you 231–232). NMR is used to detect and because a lot of the proteins that we give the drug,” says Gallatin. “We are define the location of weak binding have discovered are intracellular,” looking at acute or events; the weak binders are then says W. Michael Gallatin, Vice acute exacerbation. There’s a pretty linked together to make a tight- President and Scientific Director. nice window of therapeutic utility binding drug. “I won’t put it forward From its beginnings in 1990, that doesn’t cause the patient to as a panacea for all drug-targets,” says ICOS has focused on the immune become immunocompromised.” In Gallatin, “but it can be very powerful.” system and, more specifically, cellular clinical trials, he says, “infection adhesion and signal transduction. It hasn’t been a significant issue.” A broad approach has reduced the risks by increasing For chronic disease a more Of ICOS’s anti-adhesion drugs, only the numbers: isolating multiple specific agent is needed. One LeukArrest™ is in multiple clinical members of a given protein family to candidate is ICM-3, a humanized trials. That picture is likely to define more specific drug targets, and antibody to ICAM-3. The integrin change, however, as the company’s selecting proteins that are potential ligand ICAM-3, discovered by ICOS resources and research expand. “We targets in multiple diseases. Some of researchers, is important in the run a broader profile of clinical trials those diseases — such as heart attack interaction between T cells and than is usual because we would and stroke — are not usually thought antigen-presenting cells that leads to rather be data driven,” says Gallatin. of as problems of the immune T-cell activation. ICM-3 is in phase “I don’t think there is one uniform system. Even more distant II trials for the treatment of , algorithm that really substitutes for conceptually is a Viagra-like drug that a disease in which activated T cells scientific empiricism.” was the focus of a huge deal recently induce abnormal skin growth. Once the results of the phase II cemented with Eli Lilly & Company. Next in the adhesion pipeline trials are in, Gallatin promises the come two ICOS discoveries: CD11d company will be “draconian” in Blocking adhesion (or Alpha d) and ICAM-5. As ICAM-5 selecting only the most promising lmmune cells do most of their is found predominantly on drugs and indications for the far more disease-fighting in tissues. They get hippocampal neurons its role in extensive and costly phase III trials. into tissues, and out of the neurological disease is being “We say repeatedly that we don’t R24 Chemistry & Biology 1999, Vol 6 No 1

expect all of our phase II’s to go side effects of nausea and sedation MDC in AIDS high on our list of forward,” he says. seen with other PDE4 inhibitors. clinical candidates.” Jay Levy, a chemokine researcher The next Viagra? Interfering with the signals at the University of California at San In 1991, ICOS signed an agreement Communication in the immune Francisco, agrees. “Most people are with Glaxo Wellcome to isolate system is not all tactile; soluble finding [MDC] just isn’t produced in multiple phosphodiesterases (PDEs), messengers are also common. In 1995, sufficient amounts to play a clinical the enzymes that degrade cyclic ICOS scientists discovered platelet- role,” he says. nucleotides. Gallatin explains that the activating factor acetylhydrolase companies did not have a particular (PAF-AH, now Pafase™), which Creative financing application in mind. “The general inactivates an important inflammatory ICOS has managed to keep all or most premise was that cyclic nucleotides are messenger. Pafase™ is in phase II of the rights to its drugs even as the so important as general regulators of trials for three inflammatory drugs advance through increasingly human physiology, so there were conditions including . expensive trials, in part because of its bound to be additional important Another messenger program is stellar board of directors. In addition enzymes.” focusing on chemokines, which act as to Gates, the board includes Frank Isolating multiple PDEs was a chemoattractants for T cells, Cary (former chairman and CEO of way to begin to understand PDE monocytes and neutrophils. As with IBM Corporation), James Ferguson diversity, and a first step to achieving LeukArrest™, an inhibitor of a (former chairman and CEO of General specificity. “We felt that the key for chemokine should keep immune cells Foods), Alexander Trowbridge (former the medicinal chemist was having in the blood and out of tissues. The US Secretary of Commerce), and the tools in hand to drive selectivity research approach here is, however, Walter Wriston (former chairman and to a much higher level than had been similar to the PDE program: ICOS has CEO of Citicorp/Citibank). Their done in the past,” says Gallatin. isolated multiple chemokines in a track record has no doubt made The first drug candidate to emerge somewhat random fashion, in the potential investors feel more secure, from this program is IC351 which, like hope that some of them will be and allowed the use of creative ’s Viagra, is a small molecule interesting. Gallatin says that defining financial solutions such as limited inhibitor of PDE5. Both drugs help their functions using genetics and cell partnerships and private investments men get erections by allowing the biology is slow, especially as many of under favorable terms. buildup of cyclic GMP, which causes the chemokines appear to be But not everyone is excited about the smooth muscle cells that line blood redundant (a fact that might the links between big business and vessels to relax, so the blood vessels complicate drug development). “It biotech. DenounceNewsWire dilate. ICOS hopes that IC351 will could take you a long time to do (www.denounce.com), a parody of prove superior to Viagra based on its knockouts for all the possible targets, news services such as Business Wire, lack of interaction with PDE6, which so it could be faster to do high- used the Gates–ICOS link as is closely related to PDE5. Inhibition throughput screening to get small inspiration for a fictional press release. of PDE6 by Viagra is thought to cause molecules, which can then be used as The release states that Microsoft and the blue tinge in vision experienced by probes to define the biology.” ICOS have discovered a that some Viagra users, as PDE6 is Gallatin is particularly interested causes a partiality for Macintosh involved in visual transduction. in one chemokine discovered by computers, and that testing for the IC351 is still in phase II trials, but ICOS, dubbed -derived gene in schools is imminent. ICOS that hasn’t stopped Lilly from giving chemokine (MDC). MDC selectively may not be pleased that it was ICOS a hefty $75 million up-front recruits the TH2 class of T cells, described in the release as a company payment for the rights to 50% of any which are prominent in cell-mediated that “secretly designs, develops and IC351 revenues. The two companies reactions such as asthma. MDC’s markets pharmaceuticals for Microsoft have formed an equal partnership to fame increased when a team at the Corporation’s use in curbing further develop the drug. The deal University of Maryland at Baltimore competition.” But considering that was unusual both for the size of the claimed that it was the substance Microsoft was described as “that payment (given the early stage of secreted by CD8(+) cells that can freight train you always dreaded in IC351 testing) and for the retention suppress HIV infection. Gallatin and your dreams,” ICOS is still faring by ICOS of sales rights and not just others are not convinced. “I’m not relatively well in the land of corporate royalties. personally sure that there is as communications. The next candidate in the PDE significant a connection between program is PDE4, which has been MDC and AIDS as was originally William A. Wells implicated in asthma. Gallatin proposed in the Gallo article,” says 1095 Market Street #516, San Francisco, believes the ICOS drug will lack the Gallatin. “We would not consider CA 94103-1628, USA; [email protected].