INVITATION LETTER

Following the success of prior conferences, Korean American Society in Biotech and

Pharmaceuticals (KASBP) cordially invites all members and friends to the 2014 KASBP Fall

Symposium, hosted by KASBP, Daewoong Pharmaceutical Co. Ltd., and Green Cross Co., and

sponsored by KHIDI, KSEA, and KUSCO. The topics of this symposium are focused on general

issues in drug discovery and development with the following formats to share experiences and

expertise of the speakers with the attendees and among the attendees.

a. Forum A

Recent trend in oncology drug discovery, cell therapy, pre-formulation and rare disease

drug development presented by the scientists in Pharmaceutical R & D and Non-profit

research Organization

b. Forum B

New topics related to Marketing and regulatory topics such as QbD (Quality by Design)

application, and antifungal and antibacterial drug development

c. Round Table Discussion

Small group discussion between researchers in academia and industry to understand the

drug R&D and approval processes in the pharmaceutical industry

d. Job Fair

An open job fair for attendees to have a chance to meet the hiring managers and

representatives from Korean pharmaceutical companies or life science research institutes

This symposium will focus on current trends in drug discovery and highlighting

professionals in biotech and pharmaceutical industries. This year, the symposium has

successfully recruited outstanding speakers and panels to cover the topics described above.

Additionally, a distinguished Korean-American scientist Kinam Park, Ph.D. (Purdue University)

will be awarded with KASBP-Daewoong Achievement Award based on his contribution to drug

discovery and development. He will give a keynote speech with a title, “More than I thought I

could be” during the symposium. The symposium also offers a round table discussion with

pharmaceutical industry and academia professions to provide valuable career development tips

to young scientists.

One of the meaningful events is presenting the KASBP-Daewoong and KASBP-Green Cross

fellowship awards to young scholars such as graduate students and post-docs who exhibit

excellence in research. This symposium will provide an opportunity for members to establish

professional networks, and share information and experiences amongst members in pursuit of

excellence in research and development.

2014 KASBP Fall Symposium Organizing Committee

2

SYMPOSIUM SCHEDULE AT A GLANCE

November 7, 2014, Friday

03:00 pm – Job Fair / Exhibition

05:30 pm – 06:30 pm Registration

06:30 pm – 06:50 pm Opening and Congratulatory Remarks

06:50 pm – 07:30 pm Dinner

07:30 pm – 07:40 pm Award Ceremony

07:40 pm – 08:40 pm Keynote Speech

08:40 pm – 09:00 pm Sponsor Talk 1: Daewoong

09:00 pm – 09:20 pm Sponsor Talk 2: Green Cross

09:20 pm – 10:20 pm Round Table Discussion A (Pharma industry - Academia)

November 8, 2014, Saturday

07:00 am – 08:30 am Round Table Discussion B

(Regulatory Perspectives in Drug Approval Process)

08:00 am – 09:00 am Registration & Light Breakfast

08:50 am – 09:00 am Opening Remarks

09:00 am – 10:10 am Forum A1 Presentation

10:10 am – 10:25 am Sponsor Talk 3: KSEA

10:25 am – 10:45 am Coffee Break

10:45 am – 11:55 am Forum A2 Presentation

11:55 am – 12:30 pm Award Presentation – Six Oral Presentations by Fellowship awardees

12:30 pm – 02:45 pm Photo time, Lunch, & Poster Viewing

02:45 pm – 03:00 pm Sponsor Talk 4: KUSCO

03:00 pm – 03:40 pm Forum B1 Presentation (Panel discussion)

03:40 pm – 04:00 pm Coffee Break

04:00 pm – 05:10 pm Forum B2 Presentation

05:10 pm – 05:30 pm Closing Remarks

06:00 pm – 08:30 pm Dinner & Networking

3

SYMPOSIUM SCHEDULE IN DETAIL

November 7, 2014 (Friday)

Job Fair & Exhibition 3:00 pm ~

Coordinator: Sahee Kim (RevHealth, LLC), Dongweon Song (Novartis)

Registration & Reception Cocktail

5:30 pm ~ 6:30 pm

Coordinators: Jun Hyuk Heo (Merck), Alex Kim (Merck), Dahea You (Rutgers University)

Opening & Congratulatory Remarks and Dinner

6:30 pm ~ 7:30 pm

Coordinator: KASBP President-Designated: Jae Uk Jeong, GSK

Opening Remarks

KASBP President: Youngsun Kim, VaxInnate

Congratulatory Remarks

Daewoong Pharmaceutical Co.: President, Jong-Wook Lee

Green Cross Corp.: Executive Vice President, Eun Chul Huh

KHIDI USA: General Director, Jung-hoon Woo

Award Ceremony

7:30 pm ~ 7:40 pm

KASBP-Daewoong Achievement Award

Keynote Speech

7:40 pm ~ 8:40 pm

Award Lecture (KASBP-Daewoong Achievement Awardee 2014)

“From Pills to Nanoparticles: The 10X Progress in Drug Delivery Research”

Kinam Park, Purdue University

Sponsor Talk

8:40 pm ~ 9:20 pm

Daewoong: “Daewoong's Global Strategy”

Sang Ho Lee, Head of New Drug Development Lab.

Green Cross: “Global project and R&D pipeline of Green Cross”

Young-Seoub Park, Deputy General Manager, Research Planning Team

Round Table Discussion A

9:20 pm ~ 10:20 pm

Pharma industry – Academia, and Career Development

Chair: Chang-Sun Lee, PTC Therapeutics

Networking 9:20 pm ~ 11:45 pm

4

November 8, 2014 (Saturday)

Round Table Discussion B

7:00 am ~ 8:30 am

Regulatory Perspectives in Drug Approval Process

Chair: Yun H. Choe, Lucas & Mercanti, LLP

Registration & Breakfast

8:00 am ~ 9:00 am

Coordinators: Jun Hyuk Heo (Merck), Alex Kim (Merck),

Dahea You (Rutgers University)

Opening Remarks

8:50 am ~ 9:00 am

Program Chair: K. Stephen Suh, Hackensack University Medical Center

Forum A1------Chair: KASBP-Boston President, Sean Kim, Novartis

9:00 am ~ 10:10 am

“Selectivity Challenge in Kinase Drug Discovery”

Mooje Sung, Novartis

“Immunotherapies for Cancer”

Byoung Ryu, Bluebird Bio

Sponsor Talk

10:10 pm ~ 10:25 am

KSEA: “Introduction to KSEA”

Sung Yi, Executive Director of KSEA; Portland State University

Coffee Break

10:25 am ~ 10:45 am

Forum A2------Chair: KASBP-Phila President, Younghwan Jin, GSK

10:45 am ~ 11:55 am

“Acceleration Drug Discovery and Advancing Knowledge in Huntington Disease”

Larry C. Park, CHDI Foundation

“Role of Preformulation on Biopharmaceutical Evaluation”

Hyungchul Kim, Astra Zeneca

Award Presentation-------Chair: Eunsung Junn, Rutgers University

11:55 am ~ 12:30 pm

KASBP-Green Cross and KASBP-Daewoong Fellowship Award Ceremony

Oral Presentations by Fellowship Awardees

5

12:30 pm ~ 2:45 pm Photo time, Lunch & Poster

Poster Presentation-------Chair: Eunsung Junn, Rutgers University

Sponsor Talk and Forum B1---Chair: KASBP-Connecticut President, Seungwon Chung, Pfizer

2:45 pm ~ 3:00 pm

Sponsor Talk

KUSCO: “Introduction to KUSCO”

Kiho Moon, Director

Business and Market Assessment (Panel discussion)

3:00 pm ~ 3:40 pm

“Global Pharm Market Today”

Moderator: Eun-Ju Ryu, Pfizer

Panelists: Jinhee Park (Novartis), Bokyung M. Kim (Merck),

Coffee Break

3:40 pm ~ 4:00 pm

Forum B2 -------Chair: KASBP-DC Vice-President, Sang Tae Park, Macrogen Clinical Lab.

4:00 pm ~ 5:10 pm

“Design space building for control of critical quality attributes of a model monoclonal

antibody”

Seongkyu Yoon, University of Massachusetts Lowell

“Role of Clinical Pharmacology in Antimicrobial and Antifungal Drug Development”

Seong Hoon Jang, Pharmacologist

Closing Remarks 5:10 pm ~ 5:30 pm

KASBP President: Youngsun Kim, VaxInnate

Dinner & Networking 6:00 pm ~ 8:30 pm

Minado Restaurant (Tel. 973-734-4900)

2888 New Jersey 10, Morris Plain, NJ 07950

6

KASBP-DAEWONG AWARDEE LECTURE

From Pills to Nanoparticles: The 10X Progress in Drug Delivery Research

Kinam Park, Purdue University, Departments of Biomedical Engineering & Pharmaceutics

Drug delivery systems are designed to deliver drugs in efficient

ways to maximize the efficacy of the drugs and to increase the

patients’ compliance. The history of drug delivery technologies

spans only 60 years, and during that time numerous new drug

delivery systems have been developed, and hundreds of

advanced formulations have been marketed. Over the years,

significant advances have been made, and the formulation was

improved from simple aspirin pills to the state-of-the-art

nanoparticle technologies. While the progresses made during

the last 60 years have been exciting, more breakthrough

technologies are required to treat patients with various diseases, such as cancers and diabetes.

The next 10X advances in drug delivery requires thinking in new boxes. This talk describes

history of drug delivery through the experience of one drug delivery scientist.

2006-present Showalter Distinguished

Professor

Biomedical

Engineering

Purdue University

2005-present Editor-in-Chief Journal of Controlled Release

2001-present President Akina, Inc.

1998-present Professor Biomedical

Engineering

Purdue University

1994-present Professor Pharmaceutics Purdue University

1990-1994 Associate Professor Pharmaceutics Purdue University

1986-1990 Assistant Professor Pharmaceutics Purdue University

1983-1985 Postdoc Chemical

Engineering

University of Wisconsin-

Madison

1979-1983 Ph.D. Pharmaceutics University of Wisconsin-

Madison

1975-1977 Lieutenant R.O.T.C. Korean Army

1971-1975 B.S. Pharmacy Seoul National University

7

ABSTRACT

From Pills to Nanoparticles: The 10X Progress in Drug Delivery Research

Kinam Park, Purdue University, Departments of Biomedical Engineering & Pharmaceutics

Drug delivery systems are designed to deliver drugs in efficient ways to maximize the efficacy of

the drugs and to increase the patients’ compliance. The history of drug delivery technologies

spans only 60 years, and during that time numerous new drug delivery systems have been

developed, and hundreds of advanced formulations have been marketed. Over the years,

significant advances have been made, and the formulation was improved from simple aspirin

pills to the state-of-the-art nanoparticle technologies. While the progresses made during the last

60 years have been exciting, more breakthrough technologies are required to treat patients with

various diseases, such as cancers and diabetes. The next 10X advances in drug delivery requires

thinking in new boxes. This talk describes history of drug delivery through the experience of

one drug delivery scientist.

Selectivity Challenge in Kinase Drug Discovery

Mooje Sung, Novartis

Cancer is characterized by uncontrolled cellular proliferation. The passage of cells through the

cell cycle occurs through discrete phases controlled by cyclins which appear and disappear with a

defined periodicity, in association with their Cyclin-Dependent Kinase partners. The classical

model of mammalian cell cycle, which has originated from pioneering studies of yeast genetics by

Paul Nurse et al, places specific cyclin-CDK pairs at key transition points. The model does not

differentiate between normal or abnormally dividing cells, nor does it differentiate between tissue

or cell types. Early attempts to target CDKs led to pan inhibitors and difficulty separating

cytotoxicity from efficacy. Recent progress in the understanding of the role of CDKs in the cell

cycle control demonstrated that abolishing CDK4/6 kinase activity and subsequent reactivation

of Rb in tumors inhibited tumor and growth. Therefore, a pharmacological approach to inhibition

of cyclin-dependent kinases 4 and 6 (CDK4/6) using highly selective small molecule inhibitors

has the potential to provide novel cancer therapies for clinical use. Achieving high levels of

selectivity for CDK4/6, versus other ATP-dependent kinases, presents a significant challenge.

Herein, we describe several approaches in parallel toward identifying potent and highly selective

inhibitors of both CDK4 and CDK6 with the appropriate profile.

8

Immunotherapies for Cancer

Byoung Ryu, Bluebird Bio

Cancer is the second leading cause of death in the US. To treat advanced cancers, various forms

of immunotherapies have been developed, which include immune check point inhibitors,

antibody therapies and adoptive cell therapies. A brief overview of current immunotherapies

will be presented. In particular, chimeric antigen receptor (CAR) modified T cell therapy will be

discussed in details. In the CAR-T therapy, patients’ own peripheral T cells are isolated,

engineered to express cancer targeting cell surface receptor, and the modified T-Cells are infused

back to patients. The CAR expressing T-cells are able to kill tumor cells in vivo resulting in

disease free or reduced tumor load. Most recent clinical trials using CAR-T cell against CD19

antigen have shown remarkable complete response rate (up to ~90% in cumulative data) in

refractory acute lymphoblastic leukemia patients. Potential toxicity, strategies to mitigate the

toxicity, and key players in CAR-T immunotherapy will be also discussed at the end.

Acceleration Drug Discovery and Advancing Knowledge in Huntington Disease

Larry C Park, In Vivo Research, CHDI Foundation, Inc

CHDI Foundation is a privately-funded, not-for-profit biomedical research organization devoted

to a single disease – Huntington’s disease (HD). Our mission is to develop drugs that will slow

the progression of HD and provide meaningful clinical benefit to patients as quickly as possible.

To achieve this CHDI manages a diverse portfolio of research projects through a novel virtual

model that encourages scientific collaboration to more directly connect academic research, drug

discovery and clinical development. Our activities extend from exploratory biology to the

identification and validation of therapeutic targets, and from drug discovery and development to

clinical studies and trials. We work closely with a network of more than 600 researchers in

academic and industrial laboratories around the world in the pursuit of these novel therapies,

providing strategic scientific direction and management to ensure that our common goals remain

in focus. We’ve recently had some notable progress in this regard; an anti-sense oligonucleotide

therapeutic approach that CHDI helped develop with ISIS Pharmaceuticals was recently the

subject of substantial investment from the pharmaceutical company Roche, and we are currently

working with Pfizer to evaluate their phosphodiesterase 10 inhibitor in humans. As a not-for-

profit entity we have no competitors, and our bottom line is ensuring the shortest possible time to

getting effective therapeutics to HD patients. As such, a big part of CHDI’s remit is to

collaboratively enable any researcher that is interested in working on HD by lowering the barrier

to entry through the provision of HD domain knowledge, reagents, protocols, animal models or

funding. In our role as a collaborative enabler, CHDI seeks to bring the right partners together to

identify and address critical scientific issues to increase the understanding of HD and hasten the

development of therapeutic approaches to clinical evaluation as rapidly as possible.

9

Role of preformulation on Biopharmaceutical Evaluation

Hyungchul Kim, Astra Zeneca

The preformulation is the first step of activities to design an optimum drug delivery system of

drug candidates which involves multiple skill areas such as solid state, formulation, analytical

and biopharmaceutics. The goals of preformulation are to characterize the physicochemical

properties of drug substances and understand the fundamental variables and their relationship of

performance. Developability report of drug candidates provides risk assessment, mitigation plan,

and clinical formulation strategy as early as possible to reduce expenditure in the development

process. The role of preformulation during drug discovery and early development stage will be

described and the impact of a thorough understanding physical form on a pre(clinical)

formulation development and role of in silico simulation tool will be presented through case

studies.

Global Pharm Market Today: Panel Discussion

Eun-Ju Ryu, Pfizer (Moderator)

Jinhee Park, Novartis

Bokyung Michelle Kim, Merck

The global pharmaceuticals market is worth US$300 billion, and expected to increase to US$400

billion by 2016. As the market continues to expand, traditional mass marketing and block buster

approach are no longer valid to capture the benefit of this rapid growth, but target market

approach with innovative value added service marketing become increasingly critical for the

business success. As the market moves quickly towards high price/small volume specialty

drugs, how to maximize patient access to the new drugs while maintaining optimal pricing is one

of the key questions we need to ask in today’s marketing as well as selection of target

development programs.

We hope to cover some major changes in global marketing and market access perspectives during

this session. We also briefly discuss ‘license-in/out’ opportunities from the business development

and commercialization perspective since this links to a larger business question, ‘what is the

added value from this deal?’

10

Design space building for control of critical quality attributes

Of a model monoclonal antibody

Seongkyu Yoon, Department of Chemical Engineering, University of Massachusetts Lowell

Quality by design is an innovative approach introduced by FDA, which ensures the quality of the

product by maintaining tight quality standards. According to ICH Q8 “Quality cannot be tested

into product i.e. Quality should be build in by design”. Exploration of design space can set the

control guidelines for process objectives such as titer and product quality. Herein, we used

experimental design approach to study eleven process variables in monoclonal antibody

production. It was found that engineering changes significantly impact the glycan profiles of the

monoclonal antibodies. Regression models were built for Critical quality attributes (CQA),

Integrated Viable Cell Density (IVCD) and producttiter. Design space was explored using Monte

Carlo simulation. Optimum operating conditions and CQA specifications were determined by

exploration of design space. Current study indicates that specifying the optimum

operatingconditions can reduce risk of failure.

Keywords: Design of experiments (DoE), Monoclonal Antibody, Quality by Design (QbD),

Glycan Profiling, Critical quality attributes (CQA), Integrated Viable Cell Density (IVCD).

Unmet Medical Needs, Challenges, and Role of Clinical Pharmacology in Antibacterial and

Antifungal Drug Development

Seong Hoon Jang, Pharmacologist

There are continuous and urgent unmet medical needs for new antibacterial and antifungal drugs

for the treatment of patients infected with pathogenic microbes resistant to currently available

drugs. However, antibacterial and antifungal drug development has been declined because of

many reasons including economic issues, the inherent challenges of studying a therapeutic for

infectious disease, and scientific issues related with clinical trial designs. Several activities and

initiatives to facilitate the development of new antibacterial and antifungal drugs have been

undertaken by public agencies including the FDA, the NIH, and the CDC. These activities and

initiatives include establishing (a) streamlined clinical trial design to evaluate the efficacy of

antibacterial and antifungal drugs against drug-resistant pathogenic microbes, (b) biomarkers for

adequate efficacy endpoints and rapid diagnostics of antibacterial/antifungal susceptibility, and

(c) incentives to encourage antibacterial and antifungal drug development. In presentation,

current challenges and future considerations in antibacterial and antifungal drug development

will be discussed. In addition, it will also be discussed how to apply animal and/or patient

PK/PD data to support clinical efficacy of antibacterial and antifungal drugs as well as to select

clinically effective doses.

The opinions and information in this presentation are mine, and do not represent the views and/or policies

of the U.S. Food and Drug Administration.

11

2014 FALL KASBP FELLOWSHIP RECIPIENTS

SWI/SNF-mutant cancers depend upon non-catalytic activity of EZH2

Kimberly H. Kim,, Dana-Farber Cancer Institute, Dept, of Pediatric Oncology, Harvard University

Inactivating mutations in the subunits of SWI/SNF ATP dependent chromatin remodeling

complex has been associated with malignant transformation of both pediatric and adult cancers

indicating that the SWI/SNF complex functions as major tumor suppressors. Over the past 18

months, recent human genetic screen revealed that the subunits of the SWI/SNF complex are

specifically inactivated in various types of cancers including lung, breast, bladder, endometrial,

ovarian, and more cancers. Additionally, mouse modeling experiments demonstrate profound

tumor formation following Snf5 inactivation. Mechanistically, we have shown that the

inactivation of SNF5 caused elevated expression of EZH2, a subunit of Polycomb complexes, and

that Polycomb target genes were repressed with increased level of H3K27-trimethylation in SNF5-

deficient fibroblasts and cancers. While these data have established a significant reversal

relationship between the SWI/SNF and Polycomb complexes in regulating growth and

preventing oncogenic transformation, the reason why each subunit is associated with distinct

cancer spectra and whether similar antagonism between two epigenetic regulators present in the

wide spectrum of cancers containing inactivating mutations in subunits of the SWI/SNF complex

are largely unknown.

Interestingly, recent studies support the concept that imbalanced epigenetic antagonism between

SWI/SNF chromatin remodelers and Polycomb cause disruption of lineage-specific gene

expression programs. Thus, we hypothesize that imbalanced epigenetic antagonism between

the SWI/SNF and Polycomb complexes cause oncogenic transformation causing disruption of

lineage-specific gene expression programs. Our goal is to define the mechanism on how

mutations of SWI/SNF chromatin remodeling complex drive tumor formation and to identify

fundamentally novel therapeutic approaches for wide range of SWI/SNF mutant cancers.

In vivo cell fate tracker for stem cell therapy: from live to dead

Seung Koo Lee, Department of Radiology, Weill Cornell Medical College

Accurate tracing of cell viability is critical for optimizing delivery methods, and evaluating

efficacy and safety of cell therapeutics. A nanoparticle-based cell tracker was developed to image

cell fate from live to dead. The particle is fabricated from two types of optically quenched

polyelectrolytes, a life indicator and a death indicator, through electrostatic interactions. Upon

incubation with cells, the fabricated bifunctional nanoprobes are taken up efficiently, and the first

color is produced by normal intracellular proteolysis, reflecting the healthy status of the cells.

Depending on the number of coated layers, the signal can persist for several replication cycles.

However, as the cells begin dying, the second color appears quickly to reflect the new cell status,

and the vital status of cells, whether they are live or dead, can be identified clearly according to

their fluorescence color. Using this chameleon-like cell tracker, live cells can be distinguished

12

from apoptotic and necrotic cells instantly and definitively, and eventually feasible to image the

viability of implanted stem cells in vivo.

A draft map of the human proteome

Min-Sik Kim, McKusick-Nathans Institute of Genetic Medicine, Dept. of Biological Chemistry,

Johns Hopkins University School of Medicine

The availability of human genome sequence has transformed biomedical research over the past

decade. However, an equivalent map for the human proteome with direct measurements of

proteins and peptides does not exist yet. Here, we present a draft map of the human proteome

using high resolution Fourier transform mass spectrometry. In-depth proteomic profiling of 30

histologically normal human samples including 17 adult tissues, 7 fetal tissues and 6 purified

primary hematopoietic cells resulted in identification of proteins encoded by 17,294 genes

accounting for ~84% of the total annotated protein-coding genes in humans. A unique and

comprehensive strategy for proteogenomic analysis enabled us to discover a number of novel

protein-coding regions, which includes translated pseudogenes, non-coding RNAs and upstream

ORFs. This large human proteome catalog (available as an interactive web-based resource at

http://www.humanproteomemap.org) will complement available human genome and

transcriptome data to accelerate biomedical research in health and disease.

Arid3a is essential to execution of the first cell fate decision via direct embryonic and

extraembryonic transcriptional regulation

Catherine Rhee, Dept. of Molecular Biosciences, University of Texas at Austin

The first cell fate commitment in mammalian embryos to either the placenta-directed

trophectoderm (TE) or the embryo-destined inner cell mass (ICM) is controlled by antagonistic

actions of two transcription factors, Cdx2 and Oct4. Cdx2 represses pluripotency-associated genes,

such as Oct4 and Nanog in TE, whereas Oct4 represses TE-specific genes including Cdx2 in ICM.

Intensive studies in embryonic stem (ES) cells have identified numerous key regulators involved

in the establishment and/or maintenance of the ICM lineage. However, besides Cdx2, only a few

factors have been reported as regulators of the TE lineage, thereby limiting our understanding of

additional regulatory mechanisms required for execution of the first cell fate decision.

Arid3a, a transcription factor well-known for its requirement in B-lymphocyte development, has

recently been identified as a member of the ES cell pluripotency network. We found that Arid3a is

moderately expressed in ES cells, while its expression is significantly increased upon

differentiation. In particular, Arid3a is highly expressed in the extraembryonic tissues which

eventually give rise to the placenta, suggesting a putative role in placental development.

Consistent with these observations, Arid3a null mice undergo early embryonic death.

Here, we present evidence that Arid3a is a critical transcriptional regulator of ES to TS-like cell

trans-differentiation and plays an important role in the commitment and differentiation of TE,

rather than its specification. Induction of Arid3a in ES cells or in bona fide blastula-derived TS

13

cells triggers the TE specific gene expression program and differentiation towards subsequent

trophoblastic lineages, whereas KD of Arid3a compromises differentiation of ES cells. Arid3a OE-

generated TS-like cells when injected into 4-8 cell stage embryos, adopt an outside cell fate,

synonymous with commitment to the TE lineage. Intersection of global gene expression, genome-

wide target mapping and cellular localization studies revealed that, upon nuclear up-regulation,

Arid3a acts both directly upstream and parallel to Cdx2 to activate key TE-specific genes, while

directly repressing regulators of ES cell pluripotency, including Oct4 and Nanog. Arid3a and

histone deacetylases (HDAC1/2) associate at the protein level and selectively co-occupy

regulatory regions of pluripotent genes, suggesting a mechanism by which differential Arid3a

complexes contribute to execution of the first cell fate decision.

The role of p11: A cell type-specific regulation of depression

Ji-Seon Seo, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University

Chronic stress responses may play additive and/or causative roles in the development of

physical or psychiatric diseases such as anxiety and depression. Chronic stress, especially, is

known to induce functional and structural changes in the medial prefrontal cortex, including the

prelimbic cortex (PrL). Chronic restraint stress suppresses glutamate receptor expression and

increases glutamate transporter expression in the PrL. Chronic stress-induced molecular, cellular,

and physiological alteration of the PrL may modulate depression phenotypes as a result of altered

connectivity and circuitry. Alteration in the PrL is seen both in rodent models of depression and

in depressed humans. Therefore, the PrL is likely to play an important pathophysiological role in

depression. However, little is known about cell type-specific molecular and cellular mechanisms

underlying these processes. Our previous studies have identified p11 (also known as S100A10)

and its binding molecules to be important regulators of depression-like states. However, the

expression and role of p11 in the PrL has not been studied. Our preliminary studies demonstrate

that both p11 mRNA and protein levels are reduced in the PrL following chronic restraint stress-

induced depression, and these effects are rescued by antidepressant treatment. We also have

found that p11 is expressed in dopamine D2 receptor-positive neurons in layer II-III of the PrL

(D2-PrL neurons). To investigate p11's role in the PrL in relation to depression, we designed an

experimental scheme to determine 1) the functional role of p11 in D2-PrL neurons in depression,

and 2) the molecular mechanisms underlying the actions of p11 in D2-PrL neurons. Current and

future studies of p11 will provide not only an understanding of molecular and cellular

mechanisms on depression, but also a framework for the development of novel antidepressant

therapies.

Nek2-dependent activation of Kif24 in the suppression of primary cilia formation and breast

cancer development

Sehyun Kim, NYU Medical Center Cancer Institute, New York University

Most mammalian cell types have a primary cilium, which is a microtubule-based projection that

14

emanates from the surface of the majority of quiescent and differentiated cells. It serves as a

cellular 'antenna' for sensing and responding to the extracellular environment. Defects in the

cilium have been shown to cause a spectrum of diseases, ranging from developmental defects to

obesity to polycystic kidneys that are collectively recognized as ciliopathies. Defects in the

primary cilium may also promote tumorigenesis, since loss of cilia is commonly observed in

multiple types of cancer. Nonetheless, whether ciliary dysfunction is a cause or a consequence of

cellular transformation is unknown. Recently, several studies have reported Nek2 as an oncogene

that is ectopically expressed in various forms of breast cancer. Nek2 over-expression leads to

increased proliferation and drug resistance, whereas depletion of Nek2 reverts these effects,

although the role of Nek2 in breast cancer development is largely unknown. We have

preliminary data showing that suppression of Nek2 leads to increased formation of primary cilia,

which significantly retards cell proliferation. Conversely, over-expression of Nek2 leads to loss of

cilia in non-transformed cell lines, suggesting that Nek2 is a negative regulator of cilia formation.

We have also identified Kif24 as a putative substrate of Nek2. Kif24 has been identified in our lab

as a centriole-bound, microtubule depolymerizing kinesin that suppresses primary cilia formation.

tractBuilding on these observations, we hypothesize that Nek2 over-expression promotes

tumorigenesis by suppressing primary cilia formation through Kif24. We have evidence

showing that deregulation of Nek2-Kif24 in breast cancer cell lines restores primary cilia

formation, suggesting that the pathway may be associated with cellular transformation and

tumorigenesis. Furthermore, inducing cilia formation in these cells led to increased cellular

quiescence, which was rescued by elimination of cilia by co-depletion of pro-ciliary genes, Talpid3

and IFT88. This suggests that primary cilia formation may antagonize the uncontrolled

proliferative trait of breast tumors, and posits Nek2-Kif24 as a novel therapeutic target against

breast cancer.

15

2014 Fall Symposium Poster Presentation

Functional imaging reveals peripheral hypersensitivity during chronic pain, secondary

hyperalgesia

Yu Shin Kim, Dept of Neuroscience, Johns Hopkins University School of Medicine

Secondary hyperalgesia (one of chronic pain conditions), heightened pain sensitivity in uninjured

tissues surrounding an injury, is widely accepted to be mediated primarily by sensitization of

spinal cord and brain neurons, a process called central sensitization. The contribution of

peripheral sensitization of primary sensory neurons to chronic pain, secondary hyperalgesia

remains controversial. Here, we have generated Pirt-GCaMP3 mice in which GCaMP3, a genetic-

encoding Ca2+ sensitive indicator, is expressed robustly and specifically in almost all primary

sensory neurons. The advantages of GCaMP3 imaging using these mice include facile, parallel

direct visualization of activity in many afferents, excellent spatial resolution, and preservation of

somatotopic organization. Application of this technique to a trigeminal chronic pain, secondary

hyperalgesia model permitted us to visualize robust neuronal hypersensitivity in nerve fibers and

endings in the skin, cell bodies in trigeminal ganglion, and central terminals in the trigeminal

spinal nucleus. Strikingly, sensitization was observed not only in injured afferents but also in

uninjured trigeminal nerves of multiple neuronal cell and fiber types. Hypersensitivity in

uninjured large-diameter neurons innervating lamina III/IV at the central terminals was more

evident than that in the corresponding cell bodies. Pirt-GCaMP3 mice thus represent a unique

tool with which to visualize primary sensory neuron activity under physiological and

pathological conditions and to reveal peripheral sensitization mechanisms associated with

chronic pain, secondary hyperalgesia. Therefore, this study creates a new way of characterizing

the physiological properties and functions for developing new pain- or other modality-specific

drug target for a treatment with few side effects.

Suppression of the mevalonate pathway by wild type P53

Sung-Hwan Moon, Dept. of Biological Sciences, Columbia University

We previously reported that mutant p53 can transcriptionally activate the mevalonate (MVA)

pathway through an interaction with a family of transcription factors called sterol regulatory

element binding proteins (SREBPs) (Freed-Pastor et al., 2012). However, whether wild-type p53

regulates the MVA pathway remains to be elucidated. Our results show that wild-type p53

represses this pathway by an unexpected mechanism.

Activation of p53 by Nutlin-3 reduced expression of the MVA pathway genes in cells harboring

wild-type p53, but not in p53 null cells. When HCT116 p53+/+ and p53-/- isogenic cancer cells

were subject to sterol starvation, expression of MVA pathway genes was found to be significantly

higher in p53-/-, compared to p53+/+, and their induction was suppressed by addition of 25-

hydroxycholesterol or by Fatostatin, an inhibitor of SREBP activation. SREBPs are held as inactive

membrane-bound precursor proteins that are activated by proteolytic cleavage to form the

16

mature polypeptides that are found in the nucleus associated with MVA genes. As assessed by

immunoblotting, loss of wild-type p53 was correlated with elevated levels of the mature form of

SREBP-2. In line with this, ChIP assay showed an elevated level of SREBP-2 occupancy at the

HMGCR promoter in p53-/-, compared to p53+/+. Importantly, maturation of SREBP-2 was

enhanced in HCT116 p21-/- and SK-HEP-1 transfected with p21 siRNAs, suggesting that p21 is

necessary for p53-mediated repression of the MVA pathway. Taken together, we propose that

wild-type p53 plays a suppressive role in the MVA pathway by maintaining mature SREBP-2 at

low levels through expression of p21.

Identifying the detrimental roles of IL-1 for host resistance against non-healing cutaneous

Leishmaniasis

Sang Hun Lee, Laboratory of Parasitic diseases, National Institutes of Health

Although infection with most L. major strains including Lm Friedlin (LmFn) can successfully be

resolved in C57BL/6 mice, West African Lm Seidman strain (LmSd) causes a non-healing lesion

and severe pathology in the inoculated ear dermis by immune responses that remain to be

elucidated. We recently demonstrated that inflammasome or IL-1 deficient mice displayed

complete resistance to LmSd infection. LmSd induces stronger activation of inflammasome and

production of IL-1 than LmFn. This ability of LmSd is due to more efficient phagocytosis of

LmSd than LmFn because there is no difference in IL-1 production with the comparable

phagocytosis of both parasites using full opsonization. Moreover, in vivo disease severity of

genetic hybrids of LmSd and LmFn is correlated with the efficiency of their phagocytosis. We

also found that both L. major strains can produce two waves of IL-1 which are initiated by two

different sensors of inflammasome. The initial burst of IL-1 is produced as early as 2 hours post

infection as the result of membrane damage and K+ efflux which is sensed by NLRP3. The

identity of second wave of IL-1 is still under active study. Thus we identify a detrimental role of

inflammasome activation in host resistance against L. major Sd and describe the molecular

mechanisms underlying its non-healing pathology.

Extended serum half-life of urate oxidase by site-specific Albumination

Sung In Lim, Department of Chemical Engineering, University of Virginia

Albumin fusion/conjugation (Albumination) has been an effective method to prolong in vivo half-

life of therapeutic proteins. However, its broader application to proteins with complex folding

pathway or multi-subunits is restricted by incorrect folding, poor expression, heterogeneity, and

loss of native activity. Therefore, site-specific conjugation of albumin to a permissive site of a

target protein should expand the utility of albumin as a half-life extender. We show here genetic

incorporation of a non-natural amino acid (NNAA) followed by chemoselective albumin

conjugation to improve pharmacokinetics without significant loss of efficacy. Urate oxidase (Uox),

a therapeutic enzyme for treatment of hyperuricemia, is a homotetramer with multiple surface

lysines, limiting conventional approaches for Albumination. Incorporation of p-azido-L-

17

phenylalanine into two predetermined positions of Uox allowed site-specific linkage of

dibenzocyclooctyne-derivatized human serum albumin (HSA) through strain-promoted azide-

alkyne cycloaddition (SPAAC). The bioorthogonality of SPAAC resulted in the production of a

chemically well-defined conjugate, Uox-HSA, with a retained enzymatic activity. In the

pharmacokinetic study in mice, Uox-HSA displayed biphasic elimination kinetics with t1/2,β of

12.6 h, which contrasts to monophasic elimination kinetics of the wild-type Uox with t1/2,α of 1.4 h.

Site-specific Albumination enabled by NNAA incorporation and orthogonal chemistry

demonstrates its promise for the development of long-acting protein therapeutics with high

potency and safety.

Dynamics of DNA (hydroxyl)methylation between Intestinal Stem and Differentiated Cell

Rinho Kim, Department of Genetics, University of Pennsylvania

DNA methylation is an epigenetic modification involved in development and cancer. 5-

methylcytosine (5mC) can be oxidized to 5-hydroxymethylcytosine (5hmC) by the TET 1-3

enzymes in mammals. It is known that lacking Tet enzymes are involved in impaired leaning and

memory in brain and hematopoietic cancer, their role in intestinal epithelial renewal remains

unknown. Here, we found that 5hmC was enriched in the differentiated regions using

immunochemistry. Next, we performed immunoprecipitation for hydroxymethylated DNA

followed by high-throughput sequencing in Lgr5-expressing stem cells and differentiated cells. A

group of genes that acquire 5hmC in differentiated cells was mainly related with metabolic

processes and associated with increased expression. Loss of Tet1 in intestinal crypt cause more

cysts and inhibits intestinal enteroid differentiation. These data suggest that conversion of 5mC to

5hmC might be a novel mechanism contributing to intestinal health and a good target for colon

cancer drug development.

Analysis of Gut Commensal IgA Coating in Antiphospholipid Syndrome

Woojin Kim, Department of Immunobiology, Yale School of Medicine

Background: The mucosal barrier is known to be “leaky” in gut autoimmunity. Consistent with

this phenomenon, recent studies showed a markedly abnormal IgA coating of fecal bacteria in

patients with inflammatory bowel disease. The IgA coating in non-gut autoimmune diseases,

however, is unknown. The antiphospholipid syndrome (APS) is an autoimmune thrombophilia

that is manifested by vascular thrombosis and recurrent miscarriages. Various pathogens have

been associated with transient antiphospholipid antibody production. We hypothesized that

members of the gut microbiota could represent a chronic trigger in antiphospholipid-positive

patients and that they exhibit heightened adaptive immune responses to the microbiota. The

objective of this study was to examine levels of IgA-coated fecal bacteria in APS patients over

time and profiling the microbial community composition.

Methods: 32 subjects were included thus far in this study: 15 APS patients, 5 patients with non-

autoimmune thrombotic states, and 12 healthy normal donors (total of 17 controls). Stool and

18

blood was collected longitudinally at three monthly time points. Dietary and medication changes

were recorded at each visit. Plasma samples were analysed for β2-glycoprotein I antibodies by

ELISA. Fecal DNA was isolated using a bead beater (Biospec) and phenol-chloroform extraction,

then PCR-amplified using barcoded primers targeting the V4 region of the 16S rRNA gene.

Samples were sequenced using 2x250bp paired-end reads on an Illumina MiSeq instrument. In

parallel, fecal homogenates were stained with PE-conjugated anti-human IgA prior to

fluorescence-activated cell sorting.

Results: The average of IgA-coated fecal bacterial levels in APS patients was 17.7% compared to

11.2% in controls. The range of IgA coating was larger in APS subjects (2.3 to 49.2%) as opposed

to control subjects (2.9 to 21.4%) suggesting heterogeneity within the APS group. The differences

between APS and controls were however statistically significant (p=0.03). Incidentally, we also

noted among the control group one patient with IgA deficiency without any fecal IgA coating of

bacteria that was excluded from this analysis.

Conclusion: Our preliminary analysis demonstrated marked interindividual variation of IgA

coating among the gut microbiota of APS patients. Importantly, the average fraction of IgA-

coated gut bacteria from APS patients was significantly higher than that of controls, supporting

that several APS patients mount a stronger adaptive immune response to the microbiota. We

hypothesize that this phenomenon is either due to an intrinsically heightened host response or a

“leaky gut barrier” with secondary IgA overproduction. To our knowledge, this study represents

the first examination of fecal IgA coating in patients with non-gut autoimmunity that warrants

16S ribosomal RNA profiling of IgA-coated gut commensals.

MnO-catalyzed synthesis of quinoxalines derivatives as bioactive compound

Aram Kim, Department. of Bioengineering, Temple University

Quinoxaline derivatives are nitrogen containing heterocyclic compounds that have been utilized

as dyes, organic semiconductors, electroluminescent materials, and pharmacologically active

materials. In the context of human health and controlling biological processes, quinoxalines

exhibit antitumor, antiviral, antibacterial, antimicrobial, and anti-inflammatory activities

according to published results.

Iodine, copper, palladium, bismuth powder, zeolites, and graphites, in particular, have been

utilized as catalyst systems that can be employed as synthetic tools during the production of

quinoxalines.

This presentation will highlight the usage of multipodal manganese oxide nanocrystals as catalyst

materials during the synthesis of quinoxaline derivatives involving α-hydroxy ketones and 1,2-

diamines. Manganese oxide nanocrystals - synthesized through the thermal decomposition of a

Mn-oleate complex - are single crystalline materials with uniform multipodal structures (the

average distance between two pods are 47 ± 2 nm).

The as-synthesized bioactive quinoxaline derivatives will be subject to a future study involving in

vitro biological activities.

19

Site-Specific Labeling on Ghrelin Receptor via Genetically-Encoded Unnatural Amino Acid

Minyoung Park, Sakmar Laboratory,The Rockefeller University

The ghrelin receptor (GhR), a class A G protein-coupled receptor (GPCR) is a key player in

regulating energy homeostasis. The relationship between GhR and its endogenous ligand, ghrelin,

thus has been investigated as a drug target for treating obesity and related diseases. However,

until now there is no available marketed therapeutic targeting the ghrelinergic system primarily

due to the lack of molecular level of knowledge of the GhR signal pathways. We therefore

decided to develop a tool to analyze interactions among components comprising the GhR

signalosome (e.g., GhR, ligands, G proteins, etc.). In our present study, constitutively active GhR

with its various ligands serves as a model system. After genetically encoding the unnatural amino

acid, p-azido-L-phenylalanine (azF), site-specifically in GhR expressed in mammalian cell, we

characterized and identified functional azFGhR variants. Using bioorthogonal labeling approach

via strain-promoted alkyne-azide cycloaddition we fluorescently labeled selected functional azF-

GhR variant and further confirmed that these labeled receptors remained functionally active in

detergents by using fluorecence-based assays. Complementing emerging information from static

crystal structures of heavily modified GPCRs, our labeling strategy will provide a straightforward

way of uniformly labeling target GPCRs at specific sites suitable for single molecule fluorescence

studies to monitor dynamic conformational changes of GhR with minimal perturbation. With

facile applicability to other GPCRs and effector proteins, this type of labeling approach can be

used to spatially dissect signaling pathways of GhR, ultimately allowing us to design fine-tuned

drugs for treating “diabesity” syndromes

20

AWARDEES

2014 AWARDEES (FALL)

KASBP-DAEWOONG ACHIEVEMENT

Kinam Park, Ph. D. Purdue University

KASBP-DAEWOONG FELLOWSHIP

Dr. Kimberly H. Kim, Harvard University

Dr. Seung Koo Lee, Weill Cornell Medical College

Dr. Min-Sik Kim, Johns Hopkins University

KASBP-GREENCROSS FELLOWSHIP

Catherine Rhee, University of Texas at Austin

Dr. Ji-Seon Seo, The Rockefeller University

Dr. Sehyun Kim, New York University

PAST AWARDEES

KASBP-DAEWOONG ACHIEVEMENT

2009 Choung Un Kim, Gilead Sciences, Inc. (Kainos Medicine Inc, Korea, Current)

2010 Chung K. (David) Chu, University of Georgia

2011 Sung-Hou Kim, University of California, Berkeley

2012 Dennis Choi (MD, PhD) Stony Brook Medicine and Stony Brook University

2013 Joseph Kim Inovio Pharmaceuticals

KASBP-DAEWOONG SCHOLARSHIP

2006 James J. Pai, Schering-Plough (Handok Pharmaceuticals, Korea, Current)

2007 Young-Whan Park, Merck (National Cancer Center, Korea, Current)

2008 Young-Choon Moon, PTC Therapeutics

2009 Hong-Yong Kim, Novartis

21

PAST AWARDEES (cont’d)

KASBP-DAEWOONG FELLOWSHIP

2006 Jaeki Min, New York University; Hahn, Kim, Princeton University;

Hye-Jin Park, Rutgers University

2007 Jisook Moon, Harvard University; Sung-Yeon Park, Rutgers University;

Seok-Geun Lee, Columbia University

2008 Heung Kyu Lee, Yale University; Jung-Hwan Kim, Rutgers University;

Min Sik Kang, Columbia University

2009 Jin-Ah Park, Harvard University; Je-Min Choi, Yale University;

Deok-Ho Kim, Johns Hopkins University

2010 JungMin Ki, Rockefeller University; Hyung-Wook Kim, NIH;

Se Jin Ahn, Harvard University

2011 Muri Han, University of California, LA; Hwanjong Jang, Boston College

2012 Jeong Ho Chang, Columbia University; Jaewoo Choi, Oregon State University

2013 Jang Eun Lee (University of Pennsylvania), Eun Chan Park (Rutgers University)

KASBP-HANMI FELLOWSHIP

2011 Hyung Jin Ahn, Rockefeller University; Chang-Hoon Cho, Abramson Research Center

2012 Yuna Kim, University of North Carolina; Hyun Seop Tae, Yale University;

In Hye Lee, NIH

2013 Ju-Hee Lee, Memorial Sloan-Kettering Cancer Center;

Kyeong-Ryoon Lee, Rutgers University; Man Ryul Lee, Indiana University

2014 Young Chan Cha (Wistar Institute), Min-Kyu Cho (New York University)

Lark Kyun Kim (Yale University), Yu Shin Kim (Johns Hopkins University)

KASBP-YUHAN FELLOWSHIP

2011 Ki-Young Kim, Boston University; Joong Sup Shim, Johns Hopkins University

2012 Yeamin Huh, University of Michigan; Sookhee Bang, University of Pennsylvania;

Jungho Back, Columbia University

2013 Dong Jun Lee (University of Chicago), Ingyu . Kim (Yale University),

Ja Yil Lee (Columbia University)

2014 Seouk Joon Kwon (Rensselaer Polytech Institute), Jeongmin Song (Yale University)

Jae-Hyun Yang (Harvard Medical School), Wan Seok Yang (Columbia University)

22

PAST AWARDEES (cont’d)

KASBP-GREEN CROSS FELLOWSHIP

2011 Hansang Cho, Harvard Medical School; Sung Ung Kang, Johns Hopkins University;

Mi-Yeon Kim, Columbia University; Jae Young So, Rutgers University;

Sung-Yong Hwang, NIEHS/NIH

2012 Wonjin Jo, Drexel University; Hyo Jung Kang, Yale University;

Junghyun Lee, Columbia University; Yong Jae Lee, Yale University; Je-Hyun Yoon, NIH

2013 Yunjong Lee (Johns Hopkins University), Jun-Dae Kim (Yale University), Bae-Hoon Kim

(Yale University)

Ja Young Kim-Muller (Columbia University)

KASBP FELLOWSHIP

2009 Sang-Ho Choi, National Institutes of Health (NIH)

2010 Sang Ryong Kim, Columbia University; Tae-Sook Yoon, Rutgers University; Eun Mi Hur,

Cal. Tech.

KASBP-KSEA FELLOWSHIP

2013 Sung In Lim, University of Virginia

2014 Keun-woo Jin, Temple University

KASBP-KUSCO FELLOWSHIP

2008 Hyeon Ho Kim, National Institutes of Health; Takbum Ohn, Harvard Medical School;

Wona Joo, Wistar Institute

KASBP-KRICT FELLOWSHIP

2009 Seung-Shick Shin, Rutgers University; Un Ju Jung, Columbia University; Kyuwon Baek,

University of Pennsylvania

KASBP-KHIDI FELLOWSHIP

2010 Jae Hyun Bae, Yale University; Hee Yeon Cho, Boston College

23

2014-2015 KASBP DIRECTORS

Title Name Affiliation

President Youngsun Kim VaxInnate

President Designated Jae Uk Jeong GSK

1st Vice President Yun H. Choe Lucas & Mercanti

2nd Vice President Chang-Sun Lee PTC Therapeutics

Executive Director Suktae Choi Celgene

Science Director Eunsung Junn Rutgers University

Program Director K. Stephen Suh Hackensack Med Center

General Director Dongweon Song Novartis

Financial Director Seongwoo Hwang PTC Therapeutics

Web Director Alexander Kim Merck

1st Membership Director Jun Hyuk Heo Merck

2nd Membership Director Chris D. Lee Bristol-Myers Squibb

Public Relations Director Sahee Kim RevHealth, LLC

YG Director Diana Dahea You Rutgers University

Legal Director Elizabeth Lee Lucas & Mercanti

Auditor Hak-Myung Lee Shire

Boston Chapter President Sean Kim Novartis

Connecticut Chapter President Seungwon Chung Pfizer

Philadelphia Chapter President Yonghwan Jin GSK

Washington DC Chapter President Luke K. Oh Questcor Pharmaceuticals

Councilor Je-Phil Ryoo NAL Pharmaceuticals

Councilor Young-Choon Moon PTC Therapeutics

Councilor Hak-Myung Lee Shire

Councilor Yong-Hae Han Enzychem Lifesciences

Councilor Jae-Hun Kim IFF

24

2014-2015 SPONSORS FOR KASBP