TARGETS & MECHANISMS

CANCER’S PHOENIXBy Michael Leviten, Senior WriterAlthough recombinant IL-2 was a cancer immunotherapy long before checkpoint inhibitors came on the scene, the cytokine’s impact was limited by its potential for lethal side effects. Most attempts to lower toxicity also decreased efficacy. Now, a Washington University in St. Louis team has presented a strategy that not only avoids the adverse events but boosts efficacy, and has spun out Courier Therapeutics Inc. to take it to the clinic. Company founder Alexander Krupnick, who led the study while at Wash U, told BioCentury that while the cancer immunotherapy field has largely abandoned IL-2, with only a handful of companies still trying to tweak the protein, he thinks the approach still holds promise. Krupnick is now an associate professor of surgery at University of Virginia.Novartis AG pioneered recombinant IL-2 with Proleukin aldesleukin, which was approved in 1992 for renal cell carcinoma (RCC) and in 1998 for metastatic melanoma.According to Krupnick, Proleukin produced complete response rates that were comparable to the anti-PD-1 therapies Opdivo nivolumab from Bristol-Myers Squibb Co. and Keytruda pembrolizumab from Merck & Co. Inc., but the remissions lasted considerably longer (see “Check This Out,” page 3). “If you look carefully at the data, high-dose IL-2 cured many more people than PD-1 checkpoint blockade ever has,” he told BioCentury. The problem, said Krupnick, is that Proleukin’s side effects have “killed nearly as many people as it has cured.” He said that while the therapy works by binding and activating cancer-fighting cytotoxic lymphocytes, specifically CD8+ T cells and NK cells, it also binds endothelial cells, causing vascular leakage and lethal hypotension. In addition, IL-2 limits its own efficacy by activating Tregs, which suppress the antitumor immune response. Both drawbacks are mediated by IL-2 activating its high-affinity receptor, which contains a CD25 subunit, rather than its more moderate-affinity CD25-lacking receptor. But although mutant versions of IL-2 incapable of binding CD25 can decrease endothelial toxicity, they don’t increase efficacy. At least seven companies are still pursuing IL-2 therapies, using a variety of strategies to maintain efficacy while decreasing toxicity,

OCTOBER 27, 2016

COVER STORY1 CANCER’S PHOENIX

Courier Therapeutics may have solved the longstanding problem of how to avoid the lethal side effects of IL-2 cancer immunotherapy without compromising efficacy.

TARGETS & MECHANISMS

7 T CELL GAS, TUMOR BRAKEA trio of studies converge on a common pathway, headed by the PPAR co-activator PGC-1α, to improve T cell immunotherapies and suppress cancer metastasis.

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11 MICROBIOME GETS SKINNYXycrobe uses commensal skin bacteria as miniature drug factories for continuous, local delivery of dermal therapies.

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12 RANDOM MATHThe first catch-all diagnostic for infections.Plus: A checkpoint inhibitor for Parkinson’s disease; Blueprint takes aim at a fusion gene.

DISTILLERY

16 THERAPEUTICSInvirase analog for SLE; stabilizing Zaire ebolavirus L polymerase mRNA; resolvin D1 for a subtype of Guillain-Barré syndrome; and more…

22 TECHNIQUESMultiple gene mutations to predict responses to Yervoy; and more…

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including modifying dose or half-life, biasing signaling through specific receptor subunits, or concentrating the therapy at tumor sites (see “Everything Old is New Again,” page 4).Last month in Nature Communications, Krupnick’s team published its solution to the problem: fusing a mutant IL-2 to a viral protein that selectively binds NK cells and CD8+ T cells, which IL-2 activates to attack tumors. The group showed the compound had greater efficacy than wild-type or mutant IL-2 and an improved safety profile in mice. “In pretty high concentrations it essentially bound only cytolytic lymphocytes and activated them with almost no off-target side effects,” said Krupnick. Courier has set up shop in Houston and is backed by local investor Mercury Fund, as well as St. Louis-based Biogenerator. The newco declined to disclose the amount of funding it raised in its seed round.

GOOD WITHOUT THE BADLike previous researchers, Krupnick’s team also started with a mutant form of IL-2 incapable of binding CD25. But then his team linked the mutant IL-2 to OMCP, a protein derived from the cowpox virus that binds NKG2D, a surface receptor specific to NK cells and CD8+ T cells. “Cowpox virus has made a protein that binds only the cytotoxic lymphocytes, in effect to inactivate those lymphocytes, and the beauty of using this viral based technology is we’ve let Mother Nature and billions of years of evolution do the thinking for us,” said Krupnick.The fusion protein, dubbed OMCP-mutIL-2, is 315 amino acids long and has a 30-amino acid linker joining OMCP and IL-2 (see “Aim Intermediate,” page 5).In mice, the fusion protein activated NK cells at a 100-fold lower concentration than wild-type IL-2, and did not activate Tregs, in contrast to wild-type IL-2. The protein also induced expansion of NK cells in the mice from roughly 5% of total lymphocyte counts to nearly 50%, and caused no expansion of Tregs. Wild-type IL-2 triggered comparable expansion of NK cells, but did so at doses several times higher, nearing toxic levels. The researchers measured NK cell activation in two mouse strains that differed significantly in their NK cell responses to mimic natural human variation, and saw positive effects in both. Krupnick’s group tested the efficacy of the fusion protein in mouse models of lymphoma and lung cancer. The fusion protein was more effective at clearing lymphoma in lung and decreasing

tumor growth of Lewis lung carcinoma cells injected into mice than either wild-type or mutant IL-2. This efficacy disappeared when mice were genetically depleted of NK cells. In a mouse model of aggressive lung cancer, the fusion protein extended the time to 50% survival to 32 days from 22 days for wild-type IL-2 or 23 days for mutant IL-2. All control mice died within 30 days, while some animals in the OMCP-mutIL-2 group lived as long as 49 days.In preliminary safety studies, mice tolerated high doses of the fusion protein better than equivalent doses of wild-type IL-2.

AN ACTIVITY TIGHTROPEMichael Gladstone, a principal at Atlas Venture, told BioCentury he thinks Krupnick’s fusion protein approach “makes sense” and stands a chance of boosting the efficacy of IL-2 while reducing toxicities. However, he noted the strategy is just “one of several approaches” that have shown similar promise in preclinical models.“There’s long been interest in how to replicate some of the immune stimulatory effects of IL-2 for cancer therapy in some way that really broadens the therapeutic window,” said Gladstone.He said that therapies already in the clinic, such as Philogen S.p.A’s Darleukin or Nektar Therapeutics’ NKTR-214, could also shift the therapeutic index enough to avoid the dose-limiting

BIOCENTURY PRODUCT PROFILE

INNOVATION STAGE

Product A fusion protein comprising a mutant form of IL-2 with diminished CD25 binding, linked to the NK- and CD8+-targeting agent OMCP

Concept An IL-2-based protein that activates NK and CD8+ T cells selectively to trigger antitumor responses, while avoiding CD25-mediated toxicities

Disease Cancer

Competition Other IL-2-based immunotherapies; checkpoint inhibitors

Differentiation Decreases toxicities without sacrificing efficacy; longer remission times

Administration IV

Risks Cytokine storm syndromes

Development status Lead candidate selection

Patents Patent application filed

Company/Institution; lead investigator

Courier Therapeutics Inc.; Alexander Krupnick

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CHECK THIS OUTTherapeutic response rates for metastatic renal cell carcinoma (RCC) patients treated with high-dose IL-2 or anti-PD1 antibody therapies, broken down by complete response (CR), partial response (PR) and no response (NR). The chart shows data published in 1998 for Proleukin aldesleukin, a recombinant IL-2 marketed by Novartis AG (NYSE:NVS; SIX:NOVN), in 227 patients, and data published in 2015 for Opdivo nivolumab, an anti-PD-1 antibody from

Bristol-Myers Squibb Co. (NYSE:BMY) and Ono Pharmaceutical Co. Ltd. (Tokyo:4528), in 821 patients. Source: Courier Therapeutics Inc.; Motzer, R., et al. “Nivolumab versus everolimus in advanced renal-cell carcinoma.” New England Journal of Medicine (2015); Rosenberg, S., et al. “Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin 2: Identification of the antigens mediating the response.” Annals of Surgery (1998).

9%

10%

81%

IILL--22 ((PPrroolleeuukkiinn))

CR PR NR

1%

24%

75%

aannttii PPDD--11 ((OOppddiivvoo))

CR PR NR

Response Durability (months)α-PD-1 (Nivolumab)Interleukin-2

CRs70

CRs+PRs12

PRs13

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toxicities. Darleukin is a fusion protein consisting of IL-2 and an antibody that targets it to tumor vasculature, and is short-acting so that it can be rapidly withdrawn. NKTR-214 is a pegylated IL-2 that is long-acting and aims to avoid the high-dose toxicities of Proleukin.However, while OMCP-mutIL-2 targets at least some of the right immune cells to fight cancer and avoids known problematic cells, Gladstone thinks the jury is still out on the underlying biology. “In fairness, I think there are still some open questions about which cell populations are to blame for the toxicity and which cell populations really deserve the credit for the efficacy.”In addition, he noted there are other emerging cytokines such as IL-15 and IL-22 that may have a better therapeutic index.

In September, Atlas participated in a series A round for Delinia Inc., which is developing a form of IL-2 for autoimmunity that is engineered to have the opposite effect of OMCP-mutIL-2: selectively activating Tregs over NK or effector T cells. Dario Neri, Philogen’s CSO and professor of biomacromolecules at ETH Zurich, agreed with Gladstone that the biology of IL-2 receptors is complicated and not fully understood in humans, making it difficult to predict what sorts of toxicities the fusion protein might incur. “The toxicity of cytokines in rodents are completely different and typically less pronounced compared to humans,” said Neri.He added that because only a small percentage of a targeted protein actually reaches its intended site, while much of the

EVERYTHING OLD IS NEW AGAINIL-2-based therapeutics in clinical and preclinical development. At least seven products containing a form of IL-2 are in clinical development, and three others are in preclinical development, including CT101-IL2 from Courier Therapeutics

Inc., a fusion protein that specifically targets IL-2 to its intermediate receptor to limit immune-related toxicities. Source: BCIQ: BioCentury Online Intelligence; Courier Therapeutics Inc.

COMPANY PRODUCT DESCRIPTION INDICATION(S) STATUS

Philogen S.p.A. Darleukin (L19-IL2) Fusion of wild-type IL-2 and an L19 Fab targeting a tumor vasculature isoform of fibronectin (FN1; FN)

B cell lymphoma; melanoma

Phase III

Daromun (L19-IL2 + L19-TNF)

Darleukin combined with Fibromun (L19-TNF), an L19-tumor necrosis factor (TNF) fusion

Head and neck cancer; melanoma

Phase III

Teleukin (F16-IL2) Fusion of the human vascular targeting antibody F16 and IL-2

Merkel cell carcinoma Phase II

Acute myelogenous leukemia (AML)

Phase I

Transgene S.A. (Euronext:TNG)

MVA-MUC1-IL2 (TG4010) Recombinant Modified Vaccinia Ankara (MVA) viral vector encoding the tumor-associated antigen mucin 1 (MUC1; CD227) and IL-2

NSCLC Phase II/III

MVA-HPV-IL2 (TG4001) Modified Vaccinia Ankara (MVA) virus vector encoding human papilloma virus (HPV) types 16 E6 and E7 antigens and an IL-2 adjuvant

Head and neck cancer Phase II

Nektar Therapeutics (NASDAQ:NKTR)

NKTR-214 Pegylated IL-2 Breast cancer; colorectal cancer; Melanoma; solid tumors

Phase I/II

Provenance Biopharmaceuticals Corp.; Alopexx Oncology LLC; Merck KGaA (Xetra:MRK)

DI-Leu16-IL2 De-immunized form of the Leu16 anti-CD20 antibody fused to IL-2

Non-Hodgkin's lymphoma (NHL)

Phase I/II

Bioniz Therapeutics Inc. BNZ-1 Peptide inhibitor of IL-2, IL-9 and IL-15 Leukemia Preclinical

Pivotal BioSciences Inc. PB101 Low-toxicity analog of IL-2 Cancer Preclinical

Courier Therapeutics CT101-IL2 Recombinant fusion protein of OMCP, a orthopoxvirus-dervived protein that binds killer cell lectin-like receptor subfamily K member 1 (KLRK1; CD314; NKG2D), and a mutant form of IL-2 that does not bind the interleukin-2 receptor α chain (CD25).

Cancer Discovery

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AIM INTERMEDIATETo avoid dose-limiting toxicities associated with recombinant IL-2, researchers at Washington University in St. Louis have created a fusion protein that directly targets a mutant version of the cytokine (mutIL-2) to cytotoxic lymphocytes. Top Panel: OMCP-mutIL-2 contains a 133-amino acid mutant IL-2 protein (mutIL-2) that has two amino acid substitutions, R38A and F42K (*), linked to the 152-amino acid cowpox virus protein orthopoxvirus major histocompatibility complex class I-like protein (OMCP). The two substitutions eliminate binding to CD25, a subunit present only in the high affinity IL-2 receptor which is responsible for hypotension and edema caused by vascular leakage, allowing the fusion protein to signal via the the intermediate-affinity IL-2 receptor, which contains the CD122 and CD132 subunits. OMCP binds NKG2D, a receptor on the surface of NK cells and CD8+ T cells, allowing the fusion protein to

selectively activate the desired subset of cytotoxic immune cells. Bottom Panels: Wild-type IL-2 binds both the high-affinity (CD25/122/132) and intermediate-affinity (CD122/132) receptors to activate several types of cells expressing either receptor type, such as Tregs, endothelial cells, NK cells and other lymphocytes. In contrast, the OMCP-mutIL-2 fusion protein only activates cells that express both NKG2D and the intermediate IL-2 receptor, such as NK cells. By avoiding the high-affinity receptor, OMCP-mutIL-2 reduces toxicities associated with IL-2 activity on cells that are not cytotoxic lymphocytes. CD122 (IL2RB) - Interleukin-2 receptor β chain; CD132 (IL2RG) - Interleukin-2 receptor γ chain; CD25 - Interleukin-2 receptor α chain; IL-2 - Interleukin 2; NKG2D (KLRK1; CD314) - Killer cell lectin-like receptor subfamily K member 1

mutIL-2

OMCP

mutIL-2IL-2OMCP

NK cell

CD25 CD122 CD132 NKG2D

CD25/ 122/ 132

CD25/ 122/ 132

CD25/ 122/ 132

CD25/ 122/ 132/NKG2D

CD25/ 122/ 132

CD25/ 122/ 132

CD25/ 122/ 132

CD25/ 122/ 132/NKG2D

**

**

Tregs NK cells Endothelial cells

Other lymphocytes

Tregs NK cells Endothelial cells

Other lymphocytes

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injected protein can bind to intermediate affinity IL-2 receptors at other sites, it is possible that the fusion protein could cause different toxicities than wild-type IL-2.Neri said the fusion protein “is a mutant IL-2 and when you mutate the payload then you are also going to change the activity profile and the tolerability profile.”

Moreover, the fusion protein might be seen as foreign by the immune system. Onur Boyman, a professor in the Department of Immunology at University Children’s Hospital Zurich, said that while Krupnick’s while strategy holds promise, “the question that arises is whether the mutation of IL-2 will render the cytokine highly immunogenic and thus elicit anti-drug antibodies that neutralize the effects of the IL-2 mutant.”

According to Krupnick, the linker joining OMCP and mutIL-2 is immunogenic, but he told BioCentury that Courier has engineered a new linker that has no measurable immunogenicity. He said the company is planning GMP production of the optimized fusion protein, designated CT101-IL2, and expects to submit an IND in about one year.

COMPANIES AND INSTITUTIONS

Bristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y.

Courier Therapeutics Inc., Houston, Texas

Delinia Inc., Cambridge, Mass.

ETH Zurich, Zurich, Switzerland

Merck & Co. Inc. (NYSE:MRK), Kenilworth, N.J.

Nektar Therapeutics (NASDAQ:NKTR), San Francisco, Calif.

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland

Philogen S.p.A., Siena, Italy

University Children’s Hospital Zurich, Zurich, Switzerland

University of Virginia, Charlottesville, Va.

Washington University in St. Louis, St. Louis, Mo.

TARGETS AND COMPOUNDS

CD25 - Interleukin-2 receptor α chain

IL-2 - Interleukin-2

IL-15 - Interleukin-15

IL-22 - Interleukin-22

NKG2D (KLRK1; CD314) - Killer cell lectin-like receptor subfamily K member 1

OMCP - orthopoxvirus major histocompatibility complex class I-like protein

REFERENCES

Ghasemi, R., et al. “Selective targeting of IL-2 to NKG2D bearing cells for improved immunother-apy.” Nature Communications (2016)

Lou, K.-J. “Fixing vascular leak in IL-2 immunotherapy.” SciBX: Science-Business eXchange (2010)

“If you look carefully at the data, high-dose IL-2 cured many more people than PD-1 checkpoint blockade ever has.”Alexander Krupnick, Courier Therapeutics

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TARGETS & MECHANISMS

T CELL GAS, TUMOR BRAKEBy Karen Tkach, Staff WriterA trio of studies has converged on a common pathway, headed by the PPAR co-activator PGC-1α, to fight cancer and chronic infections by manipulating either T cell immunotherapies or the tumors themselves. While the findings reveal new biology underlying T cell exhaustion, they could also open the door to therapeutics against a hitherto under-exploited target.PGC-1α is a transcriptional co-activator commonly referred to as the “master regulator of mitochondrial biogenesis.” Its overexpression has been shown to improve outcomes in preclinical models of a wide range of diseases, including atherosclerosis, acute kidney injury (AKI) and cancer, although some studies have shown the opposite — by demonstrating high PGC-1α activity helps tumor cells thrive.The regulator lies downstream of a wide range of signaling pathways, including SIRT1, AMPK and nitric oxide (NO) synthases. As a co-activator, it helps transcription factors such as PPARγ, PPARα and NRF2 induce expression of genes that promote mitochondrial biogenesis, fatty acid oxidation, and protection from reactive oxygen species.While several PGC-1α activators and co-regulators have been targeted commercially for treatment of metabolic, cardiovascular and other diseases, no companies have disclosed clinical programs directly targeting PGC-1α.Now, three papers from groups at the University of Pennsylvania, University of Pittsburgh and Dana-Farber Cancer Institute have

found new opportunities in the PGC-1α axis for treating viral infections or cancer. In two of the studies, published in Immunity, cranking up PGC-1α expression helped T cells avoid exhaustion in cancer or chronic infection, while in the third, published in Nature, up-regulating its non-metabolic functions in tumor cells stemmed the formation of cancer metastases (see “Both Sides Now,” page 8).

FUEL FOR THE LONG HAUL In the Immunity papers, collaborating teams led by UPenn’s John Wherry and Pittsburgh’s Greg Delgoffe showed T cells battling chronic infections and cancer shared a metabolic pathology that was alleviated by PGC-1α up-regulation, which helped T cells dodge exhaustion in both settings.Wherry is director of UPenn’s Institute for Immunology and Delgoffe is a professor of immunology. The duo found the commonality when they observed that T cells in the two diseases exhibited similar phenotypes of mitochondrial dysfunction, shedding new light on a long-standing phenomenon in the field.“What was thought for many years is that when T cells become dysfunctional or exhausted, one of the consequences is that they have alterations in metabolism,” Wherry told BioCentury. “We realized that the altered metabolism occurs very early, and may actually be one of the drivers of many of the problems that exhausted T cells eventually have.”

“By reprogramming the T cell with PGC-1α, we’re creating a retirement account for it. It’s just enough to convince that cell to divert a bit more of its energy into making a few more mitochondria”Greg Delgoffe, University of Pittsburgh

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Wherry’s study focused on a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, whereas Delgoffe’s centered on a mouse model of melanoma. In both models, the researchers found chronic antigen exposure produced persistent mTOR signaling in T cells, which kept them proliferating while blocking PGC-1α activity and mitochondrial biogenesis. According to Delgoffe and Wherry, the combination of high metabolic demand and poor mitochondrial upkeep creates a T cell energy crisis. “The problem is that in the tumor microenvironment, that signal is on all the time, and so the cell never fully switches over

into saying, ‘I need to regenerate my mitochondria because I need to do this for a long period of time’,” said Delgoffe.“There are major metabolic demands to build all the bio mass needed to expand from a hundred T cells or so up to about twenty million,” added Wherry. “As you develop chronic infections or cancer, the strains on the T cell compartment don’t go away, and maintaining that kind of high demand anabolic metabolism is very stressful on the cell.” In both the infection and melanoma settings, overexpressing PGC-1α in T cells improved their mitochondrial health and increased secretion of inflammatory cytokines, and in the melanoma model, the PGC-1α-enhanced T cells shrunk tumors and extended survival more effectively than control T cells.

BOTH SIDES NOWStudies from two independent groups suggest targeting PGC-1α pathway functions could help treat cancer, either by enhancing the effects of T cell immunotherapy or slowing down tumor metastasis. On the T cell side, an Immunity paper showed engineering T cells to overexpress PGC-1α improved their metabolic health and prevented them from succumbing to exhaustion due to persistent T cell activation in a mouse model of melanoma. On the tumor side, a Nature paper showed targeting PGC-1α’s non-metabolic functions reduced metastasis in a mouse model of melanoma.Unmodified PGC-1α pathway. In cancer, endogenous or therapeutic T cells detect tumor antigens through the T cell receptor (TCR), which transmits signals through the mTOR pathway that continuously suppresses PGC-1α function. Over time, that results in impaired regeneration of mitochondria and eventually leads to T cell exhaustion and poor tumor clearance. In addition,

primary tumor cells with low PGC-1α expression have low levels of active ID2, which normally suppresses TCF4 activity, leading to high expression of pro-metastatic genes such as integrins that drive tumor metastasis.Targeting the PGC-1α pathway. In therapeutic T cells, enhanced PGC-1α expression (red oval) boosts mitochondrial biogenesis, leading to improved T cell function. In primary tumor cells, ID2 overexpression (red oval) or TCF4 knockdown (red circle) results in low integrin expression and reduced tumor metastasis without driving tumor metabolism, which can occur when tumor cells highly express PGC-1α.ID2 - Inhibitor of DNA binding 2; mTOR (FRAP; RAFT1) - Mammalian target of rapamycin; PGC-1α (PPARGC1A) - Peroxisome proliferation activated receptor γ coactivator 1-α; TCF4 - Transcription factor 4; TCR - T cell receptor

Unmodified PGC-1α pathway

mTORMitochondria

TCR

T cellTumor cell

PGC-1α

mTOR

PGC-1α

PGC-1α

ID2

TCF4

PGC-1α

ID2

TCF4

PGC-1α

ID2

TCF4

Integrins

T cell exhaustion Tumor metastasis

Improved T cell function Reduced tumor metastasis

Targeting the PGC-1α pathway

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“By reprogramming the T cell with PGC-1α, we’re creating a retirement account for it. It’s just enough to convince that cell to divert a bit more of its energy into making a few more mitochondria, which means it can persist,” said Delgoffe. Delgoffe and Wherry think the findings could be applied to improve adoptive tumor immunotherapies such as chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes. Those cells could be engineered to express PGC-1α or treated with compounds such as PPARα and PPARγ agonists, which indirectly promote PGC-1α activity. But Wherry said although those compounds are a good starting point, they are “not terribly specific” for PGC-1α activation. In addition, pathway activation could be used alongside other immunotherapy strategies addressing T cell exhaustion. “Can we combine some sort of mitochondrial boosting reagent and anti-PD-1 therapy, for instance, to relieve both of these inhibitory pathways in the T cells, or can we utilize what we know about the defects of these T cells to improve their expansion ex vivo?” said Delgoffe.In the Immunity papers blocking PD-1 improved antiviral T cell metabolism in the infection model, but checkpoint blockade did not rescue metabolic dysfunction in the melanoma model’s T cells, which face greater nutrient deprivation and a harsher microenvironment. Indeed, a separate study published by Wherry’s group in Science today suggested that overcoming T cell exhaustion could require multiple components because PD-1 blockade could not reverse the epigenetic state of exhausted T cells in a chronic LCMV infection model. The two teams are now studying PGC-1α pathway activity in patients undergoing cancer immunotherapy. “We’ve got a very active effort in a number of trials with melanoma and checkpoint blockade where we’re getting cells from both the peripheral blood and the tumor microenvironment to investigate whether these kind of effects also occur in humans,” said Wherry.University of Pittsburgh has filed patent applications covering PGC-1α-mediated T cell reprogramming and mitochondrial biogenesis for T cell therapies.

DON’T MOVEIn the Nature study, a Dana-Farber team led by Pere Puigserver showed the PGC-1α pathway could be exploited to prevent metastasis via a mechanism that was independent of metabolism.

The researchers established the connection by finding that patient-derived melanoma cells capable of invasive vertical growth expressed higher levels of PGC-1α than cells from patients with less invasive phenotypes.In a xenograft mouse model of metastatic melanoma, circulating tumor cells expressed less PGC-1α than cells that remained in the primary tumor, and knockdown of tumor PGC-1α increased metastasis. In the PGC-1α-deficient tumors, overexpressing ID2 — a downstream effector of PGC-1α — or knocking down TCF4 — a transcription factor suppressed by the PGC-1α pathway — protected mice from this metastatic phenotype.

The authors showed tumor cells with naturally low or knocked-down PGC-1α expression had high levels of several integrins and other proteins that promote metastasis. The anti-metastatic effects of ID2 overexpression or TCF4 knockdown countered this integrin gain, but neither perturbation affected tumor metabolism, suggesting the anti-metastatic activity of PGC-1α is independent of its role as an energy regulator.Cautioning that increasing tumor PGC-1α could give cancers a metabolic boost, the authors suggested therapeutics targeting ID2, TCF4 or other downstream regulators could be better options for preventing metastasis.Puigserver did not respond to requests to comment, and the patent and licensing status of the study is unknown.

NO DIRECT LINEIt’s not clear why PGC-1α has not been directly exploited by drug developers. But one reason may be the broad availability of indirect PGC-1α activators, which includes marketed compounds and nutraceuticals. For example, the generic drugs metformin and bezafibrate have been shown to activate PGC-1α via AMPK and PPARα,

“Now that we understand the PGC-1α axis a little bit, we can start using that as a fulcrum to go in and do more sophisticated kinds of manipulations.”John Wherry, University of Pennsylvania

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respectively, and several PPARγ agonists are marketed to treat metabolic diseases.Meanwhile, the SIRT1 activator resveratrol and the AMPK activator α-lipoic acid, which both increase PGC-1α function, are available as nutritional supplements.In 2008, GlaxoSmithKline plc acquired Sirtris Pharmaceuticals Inc. and its sirtuin modulators, including SRT501, an orally bioavailable formulation of resveratrol. GSK discontinued development of SRT501 after data from a 2010 Phase IIa trial showed the compound had minimal efficacy and increased the risk of renal complications in patients with multiple myeloma (MM). The pharma now has undisclosed small molecule SIRT1 activators in preclinical development. In addition, PGC-1α’s role as an integrator of many different signaling pathways may make it challenging to target directly without unwanted side effects, which means selectively targeting proteins regulated by PGC-1α could be a safer approach.Wherry thinks that could be a better option for targeting the pathway in T cell immunotherapies. “Now that we understand the PGC-1α axis a little bit, we can start using that as a fulcrum to go in and do more sophisticated kinds of manipulations of that pathway, whether it’s a drug-based approach or a genetic approach,” he said.

COMPANIES AND INSTITUTIONS MENTIONED

Dana-Farber Cancer Institute, Boston, Mass.

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.

University of Pennsylvania, Philadelphia, Pa.

University of Pittsburgh, Pittsburgh, Pa.

TARGETS AND COMPOUNDS

AMPK - AMP-activated protein kinase

ID2 - Inhibitor of DNA binding 2

mTOR (FRAP; RAFT1) - Mammalian target of rapamycin

NRF2 (NFE2L2) - Nuclear factor (erythroid-derived 2)-like 2

PGC-1α (PPARGC1A) - Peroxisome proliferation activated receptor γ coactivator 1-α

PPARα - Peroxisome proliferation activated receptor α

PPARγ - Peroxisome proliferation activated receptor γ

Resveratrol (SRT501)

SIRT1 - Sirtuin 1

TCF4 - transcription factor 4

REFERENCES

Bengsch, B., et al. “Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 Are an early driver of CD8+ T cell exhaustion.” Immunity (2016)

Luo, C., et al. “A PGC1α-mediated transcriptional axis suppresses melanoma metastasis.” Nature (2016)

Scharping, N., et al. “The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction.” Immunity (2016)

Pauken, K., et al. “Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.” Science (2016)

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MICROBIOME GETS SKINNYBy Selina Koch, Staff WriterWhile other microbiome companies battle intestinal diseases with cocktails of gut bacteria or bacteria-derived compounds, Xycrobe Therapeutics Inc. is moving beyond the gut with a platform that harnesses commensal bacteria in skin for continuous, local delivery of therapies for acne, psoriasis and other dermal diseases. Xycrobe’s platform engineers bacteria to produce therapeutic compounds, using two species that occur naturally in the skin: Propionibacterium acnes, which reside in the hair follicles and sebaceous glands of the dermis; and an undisclosed species that lives on the surface. When applied topically, the bugs home to their native layer of the skin to secrete the therapeutics. CEO Thomas Hitchcock told BioCentury using two species allows simultaneous targeting of a larger number of skin regions to deliver “more of the therapeutic to more of the tissue,” and addresses two of the biggest problems in treating skin diseases: targeted delivery and controlled dosing. “In dermatology, there are a lot of shady products that claim to deliver large proteins topically, but scientifically that’s not practical,” because large molecules typically do not penetrate the skin’s surface. And while topical small molecules — such as the retinoids used for acne — can reach the deeper layers of the skin, achieving efficacy often requires “very high doses that cause a lot of side effects.” Oral therapies are also problematic because they “go everywhere” and “create dose spikes and valleys,” he said. “Our platform allows for constant dosing, where you need it, day in and day out.”Xycrobe also engineers regulatory and biocontainment elements into the bacteria. Its version of P. acnes depends on specific nutrients that are administered separately in a cream applied regularly during treatment — a feature that prevents the bacteria from growing on other people exposed to them. “We can make it grow or not grow, live or not live, secrete or not secrete.”“No other company is doing this in the skin,” added Hitchcock.Xycrobe’s lead product, XYC3-2, is a P. acnes strain engineered to express the anti-inflammatory cytokine IL-10, which is down-regulated in the skin of acne patients. Studies in the literature suggest IL-10 could also help treat psoriasis, although delivering the molecule has been a problem.Xycrobe has unpublished studies using human skin cell-based models of acne and psoriasis showing XYC3-2 decreased disease-related inflammation compared with free IL-10 or unmodified P. acnes, Hitchcock said. “Our use of P. acnes goes 180° against what people would do for acne, because people usually try to kill P. acnes with antibiotics,” a strategy that is non-curative and leads to bacterial resistance.

The company also has data showing that the built-in growth regulator in XYC3-2 enables the dose of IL-10 to be controlled, said Hitchcock.The company expects to submit an IND for the product in acne and psoriasis in 2018 and hopes to partner the program before entering the clinic.Xycrobe will later use its platform to develop products for dermatitis and other inflammatory skin disorders, and engineer bacteria that secrete vasodilators for alopecia or anti-fungal agents.In addition, Xycrobe is developing probiotic cocktails for the consumer market that rebalance the composition of the skin microbiome to treat dermal inflammation. In August, the company, which has been incubating at Johnson & Johnson’s San Diego JLABS site, partnered its probiotic program with the pharma’s consumer division. Hitchcock said under that agreement, J&J also has first option on the IL-10 program.Xycrobe has filed three patent applications covering multiple strains of bacteria engineered to secrete therapeutics, as well as the anti-inflammatory bacterial cocktails.

COMPANIES AND INSTITUTIONS MENTIONED

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

Xycrobe Therapeutics Inc., San Diego, Calif.

TARGETS AND COMPOUNDS

IL-10 - Interleukin-10

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XYCROBE THERAPEUTICS INC., San Diego, Calif.Technology: Commensal skin bacteria engineered to secrete therapeutics Disease focus: Dermatology, inflammation, autoimmuneClinical status: PreclinicalFounded: 2014 by Thomas HitchcockUniversity collaborators: NoneCorporate partners: Johnson & JohnsonNumber of employees: 9Funds raised: $1 millionInvestors: Harman Investments, undisclosed angelsCEO: Thomas HitchcockPatents: None issued

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12 OCTOBER 27, 2016 TOC

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RANDOM MATHCompressed sensing is a mathematical theory for extracting sparse signals from a sea of noise that has spawned inventions ranging from the single-pixel camera to facial recognition software. Now, a team from Rice University has applied the concept to infection diagnostics, creating an assay that can detect virtually any pathogen from a small set of random DNA probes. By not requiring probes to be tailored for each microbe, the assay offers the first practical solution to the need for a universally applicable infection diagnostic. Compressed sensing mathematics was developed about a decade ago to efficiently reconstruct rare signals based on two essential properties: their “sparseness” relative to other signals and their “incoherence” with other signals, both of which allow them to be distinguished from noise and one another. The Rice team, led by Richard Baraniuk and Rebekah Drezek, both professors of electrical and computer engineering, reasoned that the small number of microbes in a patient sample, compared with all possible microbes, could represent sparseness, whereas the unique pattern of binding of the probes to the microbe of interest could correspond to incoherence. According to Baraniuk, that’s a major advantage over the single-pathogen diagnostics in clinical use, which rely on microbe-specific probes. “You don’t need to sample one probe per bacteria,” he said, adding that combining a specific probe for every pathogen would not only be impractical but would fail to detect newly emerging or mutated strains.By contrast, the Rice group’s approach employs a small set of non-targeted probes that can bind any microbial genome. The test homes in on the identity of the pathogen by comparing the extent to which each probe binds to the microbe’s genome with the predicted binding profiles of all known pathogens listed in databases.The strategy — dubbed the Universal Microbial Diagnostics platform — can be applied to bacteria, viruses or fungi, and is compatible with a variety of probe detection methods, including quantitative real-time PCR, DNA microarray and whole-genome sequencing. “Taking this kind of agnostic approach opened up new avenues for both probe design and measurement,” said Baraniuk. In a paper published this month in Science Advances, the group described an algorithm for converting oligonucleotide hybridization signals from DNA samples into a measure of the type and level of bacteria in a sample. Then it used a computational simulation of the assay to provide proof of concept, showing as few as 15 DNA probes could be used to detect 40 different types of bacteria. The researchers tested the theory using microarray technology and designed a set of fluorescently tagged probes, consisting of a 38-base pair, single-stranded loop for hybridization with the microbial DNA, and a 4-base pair stem conjugated to a fluorescent reporter.

The number of required probes would typically be one to two orders of magnitude lower than the number of bacteria the test aims to distinguish.

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13 OCTOBER 27, 2016 TOC

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In independent experiments using DNA samples from nine bacterial species, the group found five probes were sufficient to identify all the species with reasonable levels of accuracy and sensitivity. In additional in silico studies, the group calculated that the number of required probes would typically be one to two orders of magnitude lower than the number of bacteria the test aims to distinguish. That is in stark contrast to the one-to-one ratio of standard assays, said Baraniuk.He added that the diagnostic can be easily adapted to identify emerging bacteria via simple software adjustments, without needing to create new probes. “The really magical thing about this approach is that you just need to change the software; you don’t need to change anything about the hardware,” he said. The group is optimizing the platform’s sensitivity and validating it using blood and sputum samples from patients, after which the team will adapt it for in hospital use. Baraniuk said Rice has not filed patents on the diagnostic platform but is interested in working with companies to develop a commercial assay. Aghazadeh, A., et al. “Universal microbial diagnostics using random DNA probes.” Science Advances (2016) — Michael Leviten

PARKINSON’S CHECKPOINTWhile the checkpoint inhibitor lymphocyte-activation gene 3 (LAG3; CD223) is attracting attention in cancer — with a handful of antibodies already in the clinic — a new study suggests the receptor could be the next target for Parkinson’s disease.In a Science paper published last month, a team led by The Johns Hopkins University professor Ted Dawson found that LAG3 binds the pathological α-synuclein (SNCA) fibrils and facilitates their transmission between neurons. Blocking LAG activity prevented spread of the fibrils and reduced their neurotoxocity.Dawson is director of the university’s Institute for Cell Engineering and the Morris K. Udall Parkinson’s Disease Research Center.Although aggregation and accumulation of α-synuclein are well established contributors to neuronal degradation, how the fibrils propagate throughout the nervous system has been unclear. According to Dawson, one theory is that the fibrils are transmitted from cell to cell, similar to the way prions spread through the CNS.Now, his team has proposed a mechanism to support that notion, suggesting that after binding to extracellular α-synuclein, LAG3 helps internalize the pathogenic aggregates into a new neuron. The target emerged from a screen for transmembrane proteins that bind α-synuclein fibrils, in which the researchers identified LAG3 as the most potent and selective binding protein. Genetic deletion of LAG3 in neurons prevented internalization of the pathogenic fibrils through endocytosis and transmission of them between cells.In addition, two different anti-LAG3 antibodies were able to reduce the effect of pathogenic α-synuclein on neurons, producing a greater than 50% reduction in

Two different anti-LAG3 antibodies were able to reduce the effect of pathogenic α-synuclein on neurons.

“Taking this kind of agnostic approach opened up new avenues for both probe design and measurement.” Richard Baraniuk, Rice University

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14 OCTOBER 27, 2016 TOC

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cell-to-cell transmission and toxicity in neurons exposed to the pathogenic fibrils compared with control antibodies.In a mouse model based on injection of α-synuclein fibrils into the dorsal striatum, LAG3 knockout decreased the number of neurons that positively stained for α-synuclein, prevented the loss of dopaminergic neurons and reduced motor deficits.Although LAG3’s role in immunity is well defined, it isn’t clear whether the protein also has an immune-related role in PD or plays a different one, distinct from its checkpoint inhibitor function, in neurons.Dawson’s next steps include testing LAG3 mAbs in preclinical models of PD. “If they have benefit then this could serve as a basis to move forward to a safety/efficacy trial in PD,” he said. However, because the mAbs may not cross the blood-brain barrier, the team will also develop small molecule LAG3 inhibitors.A patent application covering the work has been filed. According to Dawson, the IP is unlicensed and unavailable for licensing. Mao, X., et al. “Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.” Science (2016)— Lauren Martz

BLUEPRINT FOR FUSIONBlueprint Medicines Corp. (NASDAQ:BPMC) and researchers at The Rockefeller University are ramping up their collaboration to develop inhibitors of a disease-driving fusion protein found in all patients with fibrolamellar carcinoma, a rare subtype of hepatocellular carcinoma (HCC) for which the only available treatment option is surgical resection.The partners joined forces in 2014, after independently identifying the fusion oncogene between protein kinase cAMP-dependent catalytic α (PRKACA) and DnaJ homolog subfamily B member 1 (DNAJB1) in patients with the cancer.In a 2014 Science study of 15 fibrolamellar carcinoma patients, a Rockefeller team found the transcript for the fusion oncogene, consisting of the N-terminus of DNAJB1 fused to exons 2-10 of PRKACA, in tumor samples — but not adjacent normal liver tissue — of all of the patients. The tumors also had higher levels of the fusion protein than normal liver tissue.In a Nature Communications study published the same year, Blueprint researchers homed in on the same fusion protein in the same cancer after using a computational method on 7,000 samples from The Cancer Genome Atlas to identify new oncogenes involving kinases.Blueprint CSO Christoph Lengauer told BioCentury that subsequent unpublished studies from The Cancer Genome Atlas and other researchers have found the oncogene in tumor samples from almost 200 additional fibrolamellar carcinoma patients, which makes it “the first genomically defined subtype of liver cancer.”Lengauer added that because the cancer occurs primarily in adolescents and young adults, whose tumor genomes are usually very stable, “we think if we have a drug against a driver, those patients have potentially the opportunity to live for a very long time.”

“It is mostly that you find that fusion, and then you don’t find really other changes, but here we know PRKACA is a driver in all patients analyzed.”Christoph Lengauer, Blueprint Medicines

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15 OCTOBER 27, 2016 TOC

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Because the fusion gene was present in all 15 patients examined by the Rockefeller researchers, they hypothesized that the genetic change was a driver of the cancer. Lengauer told BioCentury that Blueprint believed this was “a clear rationale to drug a target that is associated with the disease.”“It is mostly that you find that fusion, and then you don’t find really other changes, but here we know PRKACA is a driver in all patients analyzed,” said Lengauer.Last month, Blueprint announced its collaboration with Rockefeller and presented data for its small molecule inhibitors of PRKACA-DNAJB1 at the International Liver Cancer Association conference. Klaus Hoeflich, senior director of biology at Blueprint, told BioCentury the data showed “our compounds can very potently modulate the pathways” regulated by the fusion protein in patient-derived xenograft mouse models of fibrolamellar carcinoma. He declined to disclose other results from the program.The HCC subtype is a new indication for Blueprint, which has BLU-554, an isoform-selective inhibitor of fibroblast growth factor (FGF) receptor 4 (FGFR4; CD334), in Phase I testing for biliary cancer and advanced HCC, and three other compounds in preclinical and Phase I testing for various cancers.At least one other company is developing a therapy for fibrolamellar carcinoma: CASI Pharmaceuticals Inc. (NASDAQ:CASI) has ENMD-2076, an inhibitor of aurora kinase A (AURKA; Aurora-A) and multiple tyrosine kinases, in Phase II.Lengauer said the next steps for Blueprint and Rockefeller will be to optimize the PRKACA-DNAJB1 inhibitor and conduct safety studies. Honeyman, J., et al. “Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.” Science (2014); Stransky, N., et al. “The landscape of kinase fusions in cancer.” Nature Communications (2014)— Mary Romeo and Mark Zipkin

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16 OCTOBER 27, 2016 TOC

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INDICATION: LupusIn vitro and mouse studies identified an NMDA receptor-inhibiting analog of Invirase saquinavir that could help treat systemic lupus erythematosus (SLE). In silico screening of commercially available small molecules for compounds with structural similarities to an autoantibody-generating epitope of the NMDA receptor, followed by optimization and testing of hits in in vitro assays, identified an Invirase analog that inhibited autoantibody binding to the NMDA receptor epitope with an IC50 of 4.5 μM. In a mouse model of SLE, the compound decreased lymphocyte aggregation, tubule dilation, interstitial inflammation and other renal signs of SLE; decreased autoantibody deposition, nephropathy and sclerosis in the glomeruli of the kidneys; and increased disease-free survival compared with vehicle. Next steps include PK and safety testing of the compound in mouse models of SLE.

Roche markets the HIV protease inhibitor Invirase to treat HIV infection.

TARGET/MARKER/PATHWAY: NMDA receptorLICENSING STATUS: Patented; available for licensing and partneringPUBLICATION DETAILS: VanPatten, S. et al. J. Med. Chem.; published online Sept. 7, 2016doi:10.1021/acs.jmedchem.6b00694CONTACT: Betty Diamond, The Feinstein Institute for Medical Research, Manhasset, New Yorkemail: bdiamond@northwell.eduCONTACT: Yousef Al-Abed, same affiliation as aboveemail: yalabed@northwell.edu

AUTOIMMUNE DISEASE

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THE DISTILLERY brings you this week’s most essential scientific findings in therapeutics, distilled by BioCentury Innovations editors from a weekly review of more than 400 papers in 41 of the highest-impact journals in the fields of biotechnology, the life sciences and chemistry. The Distillery goes beyond the abstracts to explain the commercial relevance of featured research, including licensing status and companies working in the field, where applicable. This week in therapeutics includes important research findings on targets and compounds, grouped first by disease class and then alphabetically by indication.

THERAPEUTICS

INDICATION: Acute myelogenous leukemia (AML); myeloma;

lymphomaIn vitro, cell culture and mouse studies identified a dual CREBBP/EP300 inhibitor that could help treat AML, myeloma and lymphoma. Screening of a small molecule library and in vitro testing in competitive bromodomain binding assays followed by structure-based optimization of hits identified a compound that inhibited the bromodomains of CREBBP and EP300 with IC50 values of 20 and 30 nM, respectively. In twelve human AML, myeloma and lymphoma cell lines, the compound inhibited viability with IC50 values below 7 μM. In a xenograft mouse model of AML, the compound decreased tumor growth compared with vehicle. Next steps could include testing the compound in animal models of myeloma and lymphoma.

TARGET/MARKER/PATHWAY: CREB binding protein (CREBBP; CBP); E1A binding protein p300 (EP300; p300)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Crawford, T. et al. J. Med. Chem.; published online Sept. 22, 2016doi:10.1021/acs.jmedchem.6b01022CONTACT: F. Anthony Romero, Genentech, Inc., South San Francisco, Calif. email: romero.frank@gene.com

CANCER

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17 OCTOBER 27, 2016 TOC

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INDICATION: Cancer; colorectal cancer; cutaneous T cell lymphoma

(CTCL)In vitro and cell culture studies identified agonists of RXR heterodimerization that could help treat colorectal cancer, CTCL and other cancers without causing the metabolic and cutaneous side effects of Targretin bexarotene. Chemical synthesis and testing of Targretin analogs in a human colorectal cancer cell line identified 10 compounds that agonized RXR homodimerization — a requirement for RXR-dependent transcription — with EC50 values of 7.9-364.3 nM. In a human CTCL cell line, the compounds decreased proliferation compared with vehicle. In human colorectal cancer cell line-based transcription assays, seven of the compounds increased RXR-dependent transcription and nine increased the RXR-dependent/SREBP-dependent transcription ratio — a marker of Targretin-induced hypertriglyceridemia — compared with Targretin. In an HEK cell-based transcription assay, at least six of the compounds decreased RAR-dependent transcription — a marker of Targretin-induced cutaneous toxicity. Next steps include testing the compounds in animal models of breast and lung cancer.

Eisai Co. Ltd., Minophagen Pharmaceutical Co. Ltd., and Valeant Pharmaceuticals International Inc. market Targretin bexarotene, an RXR agonist, to treat cutaneous T cell lymphoma (CTCL).

Brickell Biotech Inc. and Merz GmbH & Co. KGaA have the RXR agonist BBI-3000 oral in preclinical testing to treat psoriasis and acne.

Io Therapeutics Inc. has the RXR agonist IRX4204 in Phase II testing to treat non-small cell lung cancer (NSCLC) and advanced prostate cancer and in Phase I testing to treat MS, breast cancer, pancreatic cancer, traumatic brain injury (TBI), Alzheimer’s disease (AD) and Parkinson’s disease (PD).

TARGET/MARKER/PATHWAY: Retinoid X receptor (RXR); retinoic acid receptor (RAR); sterol regulatory element binding protein (SREBP)LICENSING STATUS: Patented; one analog licensed to Tocris Biosciences Inc.; other compounds available for licensingPUBLICATION DETAILS: Heck, M. et al. J. Med. Chem.; published online Sept. 3, 2016doi:10.1021/acs.jmedchem.6b00812CONTACT: Peter W. Jurutka, Arizona State University, Glendale, Ariz.email: Peter.Jurutka@asu.edu

CANCER

INDICATION: Liver cancerPatient sample, cell culture and mouse studies suggest inhibiting KDM6B could help treat hepatocellular carcinoma (HCC). In patients, high tumor KDM6B expression correlated with poor survival. In human HCC cell lines, shRNA targeting KDM6B decreased proliferation, migration, and levels of markers of the epithelial-to-mesenchymal transition (EMT) compared with a control plasmid. In a xenograft mouse model of HCC, shRNA targeting KDM6B decreased tumor growth. Next steps could include identifying and testing small molecule KDM6B inhibitors in animal models of HCC.

TARGET/MARKER/PATHWAY: Lysine-specific demethylase 6B (KDM6B; JMJD3)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Tang, B. et al. Cancer Res.; published online Sept. 20, 2016doi:10.1158/0008-5472.CAN-15-3029CONTACT: Songqing He, Guilin Medical University, Affiliated Hospital, Guilin, China email: hesongqingdoc@126.com

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18 OCTOBER 27, 2016 TOC

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INDICATION: Nasopharyngeal cancerPatient sample, cell culture and mouse studies suggest inhibiting SPINK6 or EGFR could help treat nasopharyngeal carcinoma (NPC). In patients, high SPINK6 expression in tumors correlated with a high rate of metastasis and poor survival. In two human NPC cell lines, shRNA targeting SPINK6, antibodies against SPINK6 or EGFR, or the EGFR inhibitor Tarceva erlotinib decreased migration and invasiveness compared with normal SPINK6 expression, control antibodies or vehicle, respectively. In a xenograft rat model of NPC,Tarceva or shRNA targeting SPINK6 in primary tumors decreased the number of metastases in the liver compared with vehicle or normal SPINK6 expression. Next steps could include testing and improving safety and efficacy of SPINK6 or EGFR inhibitors in animal models of NPC.

Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., Roche and its Genentech Inc. unit market Tarceva, a small molecule inhibitor of EGFR tyrosine kinase activity, to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. The drug is also approved to treat brain cancer and in Phase III testing to treat liver cancer.

TARGET/MARKER/PATHWAY: Serine peptidase inhibitor Kazal type 6 (SPINK6); epidermal growth factor receptor (EGFR) LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Zheng, L. et al. Cancer Res.; published online Sept. 26, 2016doi:10.1158/0008-5472.CAN-16-1281CONTACT: Chao-Nan Qian, Sun Yat-sen University Cancer Center, Guangzhou, Chinaemail: qianchn@sysucc.org.cn

CANCER

INDICATION: Neuroendocrine tumorsPatient sample and cell culture studies suggest promoting GDPD5 expression or inhibiting GPC6 could help treat neuroblastoma. In patients, high tumor levels of GDPD5 and low tumor levels of GPC6, a negative regulator of GDPD5 signaling, correlated with survival. In mouse and human neuroblastoma cell lines, GDPD5 overexpression increased differentiation compared with normal GDPD5 expression. In the human cell lines, GDPD5 overexpression decreased cell motility. In one of the human cell lines, knockout of GPC6 increased differentiation and decreased cell motility compared with normal GPC6 expression. Next steps include identifying and testing GDPD5 signaling activators.

TARGET/MARKER/PATHWAY: Glypican 6 (GPC6); glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5)LICENSING STATUS: Unpatented; available for partneringPUBLICATION DETAILS: Matas-Rico, E. et al. Cancer Cell; published online Sept. 29, 2016doi:10.1016/j.ccell.2016.08.016CONTACT: Wouter H. Moolenaar, The Netherlands Cancer Institute (NKI), Amsterdam, the Netherlandsemail: w.moolenaar@nki.nl

INDICATION: Prostate cancerCell culture studies identified an inhibitor of the AKAP13-RHOA interaction that could help treat prostate cancer. Virtual screening of a compound library and in vitro testing of hits yielded a oxopyrazole-furan analog that inhibited the AKAP13-RHOA binding interaction with an IC50 of 3.6 μM. In a human prostate cancer cell line, the compound decreased proliferation, migration and invasiveness compared with vehicle. Next steps could include testing the compound in animal models of prostate cancer.

TARGET/MARKER/PATHWAY: Ras homolog gene family member A (RHOA); A-kinase anchoring protein 13 (AKAP13)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Diviani, D. et al. Cell Chem. Biol.; published online Sept. 1, 2016doi:10.1016/j.chembiol.2016.07.015CONTACT: Francesca Fanelli, University of Modena and Reggio Emilia, Modena, Italyemail: fanelli@unimo.it

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19 OCTOBER 27, 2016 TOC

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INDICATION: Prostate cancerPatient sample and cell culture studies suggest inhibiting UGT2B17 could help treat castration-resistant prostate cancer (CRPC). In CRPC patients, UGT2B17 expression in tumors correlated with disease progression. In human prostate cancer cell lines, UGT2B17 levels were higher in two androgen-independent cell lines than in an androgen-dependent cell line. In one of the androgen-independent cell lines, shRNA targeting UGT2B17 decreased proliferation compared with scrambled shRNA. Next steps could include identifying and testing UGT2B17 inhibitors in animal models of CRPC.

TARGET/MARKER/PATHWAY: UDP glucuronosyltransferase 2 family polypeptide B17 (UGT2B17)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Li , H. et al. Cancer Res.; published online Sept. 22, 2016doi:10.1158/0008-5472.CAN-16-1518CONTACT: Xuesen Dong, University of British Columbia, Vancouver, B.C.email: xdong@prostatecentre.com

CANCER

INDICATION: Cystitis; urinary tract infection (UTI) Mouse studies suggest inhibiting E. coli FmlH could help treat UTI and chronic cystitis caused by uropathogenic E. coli (UPEC). In a mouse model of chronic cystitis caused by UPEC, bacterial knockout of FmlH decreased bacterial titers in the bladder — a cause of chronic cystitis — compared with normal FmlH expression. Also in the model, immunization with a vaccine based on the FmlH adhesin domain decreased titers in the bladder and the kidneys during the chronic stage of infection compared with vehicle. Next steps could include identifying and testing FmlH inhibitors in the model.

TARGET/MARKER/PATHWAY: E. coli FmlHLICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Conover, M. et al. Cell Host Microbe; published online Sept. 22, 2016doi:10.1016/j.chom.2016.08.013CONTACT: Han Remaut, Structural Biology Research Center, VIB, Brussels, Belgiumemail: han.remaut@vib-vub.be CONTACT: Scott J. Hultgren, Washington University School of Medicine, St. Louis, Mo.email: hultgren@wusm.wustl.edu

GENITOURINARY; INFECTIOUS DISEASE

INDICATION: EbolaCell culture studies suggest stabilizing Zaire ebolavirus L polymerase mRNA could help treat Ebola. Bioinformatics analysis of the Ebola genome and NMR studies of Ebola mRNAs identified a G-quadruplex structure in the mRNA of Zaire ebolavirus L polymerase. In a mouse cell-based Ebola replication assay, a tool compound that stabilizes G-quadruplexes decreased L polymerase transcription and viral replication compared with vehicle. Next steps could include testing the compound in animal models of Ebola.

TARGET/MARKER/PATHWAY: Zaire ebolavirus L polymeraseLICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Wang, S.-R. et al. Cell Chem. Biol.; published online Sept. 8, 2016doi:10.1016/j.chembiol.2016.07.019CONTACT: Xiang Zhou, Wuhan University, Wuhan, Chinaemail: xzhou@whu.edu.cnCONTACT: Tian Tian, same affiliation as aboveemail: ttian@whu.edu.cnCONTACT: Bo Zhang, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Chinaemail: zhangbo@wh.iov.cn

INFECTIOUS DISEASE

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20 OCTOBER 27, 2016 TOC

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INDICATION: Bone repairNon-human primate and rat studies showed that a synthetic hyperelastic bone scaffold could promote spinal fusion and treat skull bone loss. The hyperelastic bone scaffold consisted of 90% hydroxyapatite and 10% poly(lactic-co-glycolic acid) (PLGA) by weight, was produced on a 3-D printer in a process that allowed incorporation of growth factors and other biologics, and had elasticity and load-bearing properties similar to those of natural bone. In a rat model of spinal fusion, implants of the synthetic scaffold containing recombinant human BMP2 at two lumbar vertebrae fused at a rate of 83% and implants without BMP2 fused at a rate of 46% compared with no fusion for implants composed of hydroxyapatite putty. In a rhesus macaque model of skull bone defects, the implants of the synthetic scaffold without BMP2 integrated with surrounding tissue and showed signs of bone growth at four weeks post-implantation. Next steps include testing the hyperelastic bone scaffold in other animal models of bone loss.

TARGET/MARKER/PATHWAY: Bone morphogenetic protein 2 (BMP2)LICENSING STATUS: Patent application filed; licensing status undisclosedPUBLICATION DETAILS: Jakus, A. et al. Sci. Transl. Med.; published online Sept. 28, 2016doi:10.1126/scitranslmed.aaf7704CONTACT: Ramille N. Shah, Northwestern University, Evanston, Ill.email: ramille-shah@northwestern.edu

MUSCULOSKELETAL

INDICATION: Cognitive dysfunctionMouse studies suggest transiently promoting KLF9 expression could help treat age-related memory impairment. In aged and middle-aged mice, transient overexpression of KLF9 in the dentate gyrus increased contextual memory compared with normal KLF9 expression. Next steps could include testing the effects of sustained or continuous KLF9 expression on memory in the aged mice.

TARGET/MARKER/PATHWAY: Kruppel-like factor 9 (KLF9)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: McAvoy, K. et al. Neuron; published online Sept. 1, 2016doi:10.1016/j.neuron.2016.08.009CONTACT: Amar Sahay, Massachusetts General Hospital, Boston, Mass.email: asahay@mgh.harvard.edu

NEUROLOGY

INDICATION: Guillain-Barré syndrome (GBS)Mouse studies suggest RvD1 could help treat the acute inflammatory demyelinating polyneuropathy (AIDP) subtype of GBS. In a mouse model of AIDP, intraperitoneal RvD1 decreased demyelination of sciatic nerves and disease duration compared with vehicle. Next steps could include evaluating RvD1 in models of other neuropathies.

TARGET/MARKER/PATHWAY: Resolvin D1 (RvD1)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Luo, B. et al. J. Neurosci.; published online Sept. 14, 2016 doi:10.1523/JNEUROSCI.0020-16.2016CONTACT: Zhi-Yuan Zhang, Nanjing Medical University, Nanjing, Chinaemail: zhiyuan.zhang@medizin.uni-tuebingen.de; zzy@njmu.edu.cnCONTACT: Zhiren Zhang, Third Military Medical University, Chongqing, China email: zhangzhiren@yahoo.com

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21 OCTOBER 27, 2016 TOC

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THERAPEUTICS

INDICATION: PainIn vitro and mouse studies identified a peptide-based MOR agonist that could help treat pain. Chemical synthesis and in vitro testing of analogs of a cyclic Phe-D-Pro-Phe-Trp peptide yielded a compound that selectively bound MOR with a Ki of 4.1 nM. In a cell-based assay, the compound inhibited accumulation of the MOR signaling mediator cAMP with an IC50 of 6.1 nM. In a mouse model of visceral pain, the compound decreased pain-related behavior compared with vehicle. Next steps could include testing the compound in additional models of pain.

TARGET/MARKER/PATHWAY: μ opioid receptor (MOR; OPRM1)LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: De Marco, R. et al. J. Med. Chem.; published online Sept. 8, 2016doi:10.1021/acs.jmedchem.6b00420CONTACT: Santi Spampinato, University of Bologna, Italyemail: santi.spampinato@unibo.itCONTACT: Luca Gentilucci, same affiliation as aboveemail: luca.gentilucci@unibo.it

NEUROLOGY

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22 OCTOBER 27, 2016 TOC

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TECHNIQUES

TECHNOLOGY: Gene profiling A panel of five microRNAs could be used for the differential diagnosis of subtypes of aggressive prostate cancer and to predict the risk of disease progression. Exon sequencing of serum samples from eight patients with aggressive prostate cancer and eight healthy volunteers identified a panel of five miRNAs — microRNA-106a (miR-106a), miR-135a, miR-200c, miR-433 and miR-605 — that were more highly expressed in patients whose cancer advanced locally or metastasized (high-risk) than in the patients whose cancer did not progress (low-risk) and in volunteers. In an independent cohort of nine patients with high-risk aggressive prostate cancer, nine patients with low-risk aggressive prostate cancer and 10 healthy volunteers, the five-miRNA panel distinguished patients from volunteers and high-risk patients from low-risk patients with 89% accuracy. Next steps include validating the results in a larger patient cohort.

DESCRIPTION: Five-microRNA panel for differential diagnosis of prostate cancer subtypes and prediction of disease progressionLICENSING STATUS: Patent application filed; available for licensingPUBLICATION DETAILS: Alhasan, A. et al. Proc. Natl. Acad. Sci. USA; published online Sept. 6, 2016doi:10.1073/pnas.1611596113CONTACT: Joshua J. Meeks, Northwestern University, Chicago, Ill. email: joshua.meeks@northwestern.edu

BIOMARKERS

TECHNOLOGY: Gene profilingMutations in SERPINB3, SERPINB4 or IFNγ pathway genes could help predict responses to Yervoy ipilimumab in melanoma patients. In a cohort of 174 Yervoy-treated patients, tumor mutations in SERPINB3 or SERPINB4 were associated with therapeutic responses and survival. In a second cohort of 104 Yervoy-treated patients, mutations in 66 IFNγ pathway genes, including interferon γ receptor 1 (IFNGR1), IFNGR2 and Janus kinase-2 (JAK-2), were associated with poor therapeutic responses. Next steps could include validating the mutations in larger cohorts.

Bristol-Myers Squibb Co. and Ono Pharmaceutical Co. Ltd. market Yervoy, a mAb against cytotoxic T-lymphocyte associated protein 4 (CTLA4; CD152), for melanoma and have the compound in Phase I through Phase III testing for various cancers.

DESCRIPTION: Mutations in serpin family B member 3 (SERPINB3), SERPINB4 or interferon γ (IFNγ) pathway genes to predict responses to Yervoy ipilimumab in melanomaLICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Riaz, N. et al. Nat. Genet.; published online Sept. 26, 2016doi:10.1038/ng.3677CONTACT: Timothy Chan, Memorial Sloan Kettering Cancer Center, New York, N.Y.email: chant@mskcc.orgLICENSING STATUS: Patent application filed; unlicensedPUBLICATION DETAILS: Gao, J. et al. Cell; published online Sept. 22, 2016doi:10.1016/j.cell.2016.08.069CONTACT: Padmanee Sharma, The University of Texas MD Anderson Cancer Center, Houston, Texasemail: padsharma@mdanderson.org

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TECHNOLOGY: Plasma markersMeasuring clonal expansion of circulating CD8+ T cells could help predict high-grade immune-related adverse events in prostate cancer patients treated with Yervoy. In a Phase II trial of 24 patients with metastatic prostate cancer who received androgen-deprivation therapy and Yervoy, treatment-induced expansion of 55 or more CD8+ T cell clones in blood samples was associated with immune-related adverse events such as high-grade transaminitis, hypophysitis and diarrhea. In an independent cohort of 11 patients with localized prostate cancer treated with androgen-deprivation therapy and Yervoy before radical prostatectomy, 9 patients who experienced high-grade immune-related adverse events had treatment-induced expansion of 55 or more CD8+ T cell clones. Next steps include validating the association in larger cohorts of Yervoy-treated patients.

Bristol-Myers Squibb Co. and Ono Pharmaceutical Co. Ltd. market Yervoy, a mAb against cytotoxic T-lymphocyte associated protein 4 (CTLA4; CD152) for melanoma, and have the compound in Phase I through Phase III testing for various cancers.

DESCRIPTION: Clonal expansion of circulating CD8+ T cells to predict risk of high-grade immune-related adverse events in prostate cancer patients treated with Yervoy ipilimumab LICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Subudhi, S. et al. Proc. Natl. Acad. Sci. USA; published online Oct. 3, 2016doi:10.1073/pnas.1611421113Contact: James Allison, The University of Texas MD Anderson Cancer Center, Houston, Texasemail: jallison@mdanderson.org

BIOMARKERS

TECHNOLOGY: Tool compoundsA phenoxybenzamide analog that inhibits PARP-10 could be useful for investigating the role of the enzyme in cancer. In vitro assay screening of a small molecule library yielded a compound that inhibited PARP-10 activity with an IC50 of 329 nM and more than 100 times greater selectivity for PARP-10 over 14 other PARP enzymes, including PARP-1, PARP-2 and PARP-3. In HeLa cells, the compound increased sensitivity to the anti-neoplastic agent Droxia hydroxyurea compared with vehicle. Next steps could include using the compound to probe the role of PARP-10 in tumor models.

Bristol-Myers Squibb Co. markets Droxia, an antineoplastic agent, to treat cancer and sickle cell anemia.

DESCRIPTION: Tool compound for probing the role of poly ADP-ribose polymerase 10 (PARP-10) in cancerLICENSING STATUS: Patent application filed; available for licensingPUBLICATION DETAILS: Venkannagari, H. et al. Cell Chem.; published online Sept. 22, 2016doi:10.1016/j.chembiol.2016.08.012CONTACT: Lari Lehtio, University of Oulu, Oulu, Finlandemail: lari.lehtio@oulu.fi

CHEMISTRY

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24 OCTOBER 27, 2016 TOC

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TECHNOLOGY: Cell modelsMicroglia-like cells derived from hPSCs could be used to model cellular pathologies in neurological diseases. The microglia-like cells were generated by plating hPSCs in a serum-free medium containing IL-34 and macrophage colony-stimulating factor 1 (CSF1; M-CSF); maintaining the hPSCs in suspension culture until they formed 3-D rope-like structures that expressed markers of early myelogenesis; isolating the 3-D structures and maintaining them in media with no passage for up to a month; then finally selecting and isolating cells that expressed two microglial markers: nuclear expression of transcription factor PU.1 (SPI1; PU.1) and membrane expression of complement receptor 3 (CR3; CD11b). The resulting microglia-like cells had a morphology transcriptome signature that closely resembled that of primary human fetal microglia. Using the method, microglia-like cells derived from human embryonic stem cells (hESCs) that expressed a mutation in methyl CpG binding protein 2 (MECP2; RTT) associated with Rett syndrome were smaller than microglia-like cells derived from wild-type hESCs. Next steps could include using the model to screen for neurological disease therapies.

DESCRIPTION: Human pluripotent stem cell (hPSC)-derived cells model microglia in neurological diseaseLICENSING STATUS: Patent and licensing status unavailablePUBLICATION DETAILS: Muffat, J. et al. Nat. Med.; published online Sept. 26, 2016doi:10.1038/nm.4189CONTACT: Rudolf Jaenisch, Whitehead Institute for Biomedical Research, Cambridge, Mass.email: jaenisch@wi.mit.edu

DISEASE MODELS

TECHNOLOGY: Structural analysesChimeric rat-human NMDA receptors could help guide the development of selective NMDA receptor PAMs for neurological diseases. The chimeric receptors were constructed by replacing the transmembrane or ligand-binding domains of various NMDA receptor subunits — including NMDA receptor NR1 subtype (GRIN1; NR1), GRIN2A (NR2A) and GRIN2B (NR2B; GluN2B) — with the corresponding segments from the rat homologs. In a human liver cell line expressing the chimeric NMDA receptors, electrophysiological analysis of the NMDA receptor pores showed that multiple NMDA agonists induced neuron potentiation in the presence of the transmembrane domains from GRIN1 and GRIN2B, whereas the PAM docosahexaenoic acid (DHA) induced neuron potentiation only in the presence of the proximal portion of the GRIN2A subunit’s C-terminal domain and the PAM pregnenolone induced neuron potentiation only in the presence of both the ligand-binding domain and transmembrane domains from the NMDA receptor subunits. Next steps could include using the results to design novel NMDA receptor PAMs.

DESCRIPTION: Analyses of NMDA receptor subunits required for interactions with positive allosteric modulators (PAMs) to guide structure-based drug designLICENSING STATUS: Patent and licensing status unavailable PUBLICATION DETAILS: Wilding, T. et al J. Neurosci.; published online Aug. 24, 2016 doi:10.1523/JNEUROSCI.0345-16.2016CONTACT: James E. Huettner, Washington University School of Medicine in St. Louis, St. Louis, Mo.email: jhuettner@wustl.edu

DRUG PLATFORMS

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25 OCTOBER 27, 2016 TOC

Evan Beckman, M.D., Global Head of Translational Medicine, Novartis Institutes for BioMedical Research

Kate Bingham, M.B.A., Managing Partner, SV Life Sciences

Bruce Booth, Ph.D., Partner, Atlas Venture

Francis Cuss, M.D., EVP and CSO, R&D, Bristol-Myers Squibb Co.

Michael Hayden, M.D., Ph.D., President Global R&D, CSO, Teva Pharmaceutical Industries. Ltd.

Reid Huber, Ph.D., EVP and CSO, Incyte Corp.

Annalisa Jenkins, M.D., CEO, Dimension Therapeutics Inc.

Tetsuyuki Maruyama, Ph.D., CSO Dementia Discovery Fund, SV Life Sciences

Antoine Papiernik, M.B.A., Managing Partner, Sofinnova

Francesco de Rubertis, Ph.D., Co-founder and Managing Partner, Medicxi

James Sabry, M.D., Ph.D., SVP Partnering, Genentech Inc.

Elliott Sigal, M.D., Ph.D., Venture Partner, NEA

Moncef Slaoui, Ph.D., Chairman, Global Vaccines, GlaxoSmithKline plc

Marc Tessier-Lavigne, Ph.D., President, Stanford University

Mads Thomsen, D.V.M., Ph.D., EVP and CSO, Novo Nordisk A/S

Jan van de Winkel, Ph.D., President and CEO, Genmab A/S

Douglas Williams, Ph.D., Co-founder and CEO, Codiak BioSciences Inc.

Keith Yamamoto, Ph.D., Vice Chancellor, Science Policy and Strategy, University of California San Francisco

Elias Zerhouni, M.D., President, Global R&D, Sanofi

SCIENTIFIC ADVISORY BOARD

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26 OCTOBER 27, 2016 TOC

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