The Center of Excellence for

Preclinical Oncology Drug R&D

EXPPERTISE AND KNOWLEDGE

Advanced gene manipulation (AGM) to assist target validation

Diversified cancer cell panel with over 1,000 lines for profiling

Comprehensive solutions for assay, screening and profiling

Animal models to support target validation, PK/PD and efficacious study

Phage display platform delivers novel therapeutic antibodies in efficiency

Integrated Oncology & Immuno-Oncology platforms and models

HD BIOSCIENCES

Partner for Your Success

Top ranked service provider supporting early drug discovery Strategic partner for several big pharmaceutical companies to fully support hit identification and

lead discovery Teamed with leading pharmas and biotech companies on oncology target discovery and

exploratory biology Diversified cancer cell collection with option of genome data for profiling and translational

research Comprehensive assay and screening platform for hit identification and lead discovery Proprietary antibody discovery platform to identify novel therapeutic antibodies

INTEGRATED SERVICES FROM TARGET TO PRECLINICAL CANDIDATE

BIOLOGY DMPK/Tox PHARMACOLOGYCHEMISTRY

Scaffold mining & design

Library design & synthesis

SAR supportLead generation &

optimizationIP support

In vivo pharmacologyAnimal models

PK/PD Efficacy MOA

Safety assessmentHistopathology

AAALAC accredited facility

Bio-analysisIn vitro ADME

In vivo PKMetabolite

identificationExploratory toxicity

Drug-drug interaction DMPK profiling

Target validation Assay development

HTS & SAR screeningFunctional profiling

Compound managementBiomarker & MOABiologics discovery

HD Biosciences, with its industry leading capabilities and highly experienced teams, has been recognized asa reliable partner for preclinical drug development as well as integrated R&D services. The combinedstrength in in vitro pharmacology, in vivo pharmacology, DMPK, medicinal chemistry and biologics discoveryhas provided comprehensive supports from early target discovery to preclinical candidate selection, leadingto the delivery of several drug candidates which are in the late stage of clinical development.

EXPERTISE AND KNOWLEDGE

Target Validation& Discovery

Oncology focused Hit ID & Lead

Discovery

Immuno-Oncology Antibody Discovery

CENTER OF EXELLENCE for Preclinical Oncology Drug Development

On the latest exciting progress on new drug development against cancer, immuno-oncology (I/O) representsa significant paradigm shift in cancer therapy, especially with the promising clinical data from checkpointmodulators. At HDB, we offer cancer drug discovery services with comprehensive I/O platforms and modelsto address the unmet needs and assist our clients to grow their immuno-oncology portfolio.

Immuno-Oncology

EXPERTISE AND KNOWLEDGE

Antigen Presenting & Immune System Activation• T cell activation (anti-CD3/CD28; super antigen/Staphylococcal

enterotoxin B (SEB));• Mixed lymphocyte reaction (MLR)• NK cell activation (anti-CD335/anti-CD2; IL-2)• T cell polarization (Th1, Th2, Th17, Treg polarization)• Monocyte differentiation (DC, macrophage)

Regulation of Immune System & Tumor Environment• Tumor infiltrated immune cells phenotype profiling (TIL)• Tumor cell/immune cells interaction (IDO inhibitor efficacy

study in T cell-HeLa co-culture system)• Immune cell migration, adhesion and chemotaxsis

Cancer Cell Killing by Immune Cells• PBMC mediated cytotoxicity• NK cell mediated cytotoxicity• Multiple choices of assay format (FACS; IncuCyte; LDH; Calcein-

AM; Label free; DELFIA® Cytotoxicity Assays)

Multi-color FACS, Multiplex of MSD, Co-culture and Primary cell-based Assays• Multiple color immune cells profiling and analysis• Multiple markers readouts and detection• Primary cells, 3D culture, organoid

• IDO1 biochemical assay• IDO1 cellular assay • TDO biochemical assay• TDO cellular assay• T cell/HeLa co-culture functional system

Time course of Trp consumption

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Multiple unique assays are available to identify both broad and selective inhibitors to IDO family

• Syngeneic models: over 30 validated lines and more

ongoing

• Humanized mice reconstitute human immune system

• STAM HCC model: STZ & diet HCC Model

• TIL profiling in tumor tissues to support MOA

• CDX model: over 100 validated models

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IDO Family Platform In vivo Models and PK/PD Supports

As the first critical step to a successful drug development, target validation provides in-depth understandingof the biological function of target in tumor initiation, progression and metastasis. Leveraging our cuttingedge Advanced Gene Manipulation (AGMTM) platform and comprehensive phenotypic characterizationoptions, HDB’s Target Validation Program aims at helping clients make quick go/no go decisions in the earlystage of drug discovery

Target Discovery & Validation

EXPERTISE AND KNOWLEDGE

Advanced gene manipulation system (AGMTM)• Provide comprehensive options for gene manipulation from in vitro, tissues of interest, to in vivo disease models• Target knockdown, knockout, knockin achieved through siRNA, shRNA, CRISPR technologies• Target overexpression: plasmid and lentiviral based gene overexpression in selected cell lines• Delivery system with non-viral and viral systems including lenti, adenoviral, AAV, etc.• Conventional and conditional manipulation of the gene in mice or isogenic cell lines

Phenotypic characterization assays• In vitro functional readouts, gene expression profiling, target MOA and pathway analysis• In vivo phenotypic characterization in CDX models• Target functional assessment in selected/broad type of cancer lines • Routine functional assays including proliferation, 3D, apoptosis, migration, etc.

Over 1,000 cancer cell lines for target validation, compound profiling and translational research• Proprietary database tools to manage information from public domain and in house programs• Covering broad range of tumor types with geographic diversity• Well-established process for cell bank management and QC

Targeted metabolite profiling• LC/MS/MS based detection of ~ 100 metabolites covering over 10 metabolic pathways• Supporting for better understanding of the complex metabolic network in cancer

CRISPR technology provides precise and easy solution for gene manipulation from in vitro to in vivo

Multiple virus systems (AAV, lenti and adenovirus systems) ensure effective and tissue specific delivery

Sophisticated phenotypic characterization assays to support functional assessment, in-depth MOA and proof of concept studies

LC/MS/MS-based targeted metabolite profiling platform to support target validation and other exploratory study in cancer metabolism

Validation of CRISPR system with GFP in cancer cells

U2OS_EGFP U2OS_naive

sgRNA -- Scramble sgRNA1 sgRNA2 --

EGFP

GAPDH

Naïve EGFP sgRNA1

As one of the breakthrough genetic engineering tools, CRISPR/CAS9 technology provides a precise andefficient way to re-write genome and fundamentally changed the way how we think about treating diseases.HDB’s CRISPR/CAS9 platform offers various options from in vitro to in vivo to support target identification,gene functional evaluation, mechanism of action as well as animal model development.

CRISPR/CAS9 Technology

EXPERTISE AND KNOWLEDGE

β-tubulin

Target A

Target B

Target C

Naïve A KO B KO C KO A/B KO A/C KO B/C KO

Single & double target knockout in selected cancer cell line Knock-in detection in monoclonal cells by PCR and endonuclease cleavage

sgRNA library virus prep and titration

H1975(EGFR-T790M/L858R) cell infection

Puromycin and sequent BIBW2992

selection

gDNA extraction, barcode

amplification and sequencing by NGS

Bioinformatics' analysis

Flowchart for sgRNA library screen to identify drug resistance related targets

Inducible Cas9 cell line generation

CRISPR/CAS9 based engineered cell line generation and characterization • Isogenic cell line generation and characterization

• Single target knockout• Double or multiple targets knockout• Large deletion (up to 300kb)• Single target knockin with point mutation• Knockin cell line generation-insertion• Knockin plus knockout cell line generation

• Inducible system to support essential gene manipulation• Multiple choice of delivery system ensure efficient knockout• Isogenic knockout or knockin cell line generation in human iPS

sgRNA library screen• Target identification and validation in context to disease and MOA• Exploration of target with combination of drug treatment• Commercial libraries and customized library• Library amplification• Drug resistance screen and synthetic lethal screen

In vivo system development• Cas9 transgenic mice system• AAV mediated model development

CRISPR based transcriptional regulation studies

Potential drug resistance related targets identified from sgRNA library screen

Fully implemented and strictly control process

• Proprietary compound management system (CPMS) provides solutions for information tracking from vials/plates, assay & screening, to data processing, output and management

• Strong IT Infrastructure with variety of data analysis tools to facilitate data recording, curve fitting, visualization and reporting

• Program progress tracking, from material logistics to data/reports delivery

Comprehensive Assay & Screening Platform

Cancer Cell Bank and Panel Screening

Cell line collection & banking

Strong support for target validation, compound evaluation and translational medicine

Over 1,000 cancer cell lines covering broad tumor types with geographic diversity

Frozen cell pellet and DNA, RNA, protein sample collection

SOP guided cell line characterization

Mycoplasma detection

Cell growth curve, doubling time

DNA profile with STR

A proprietary database including in house genomic data as well as information available from public domains

Multiple choices for functional evaluation

Proliferation assay (CTG, Cyquant, SRB, MTT)

IncuCyte label free dynamic monitoring of proliferation

3D soft agar assay & spheroid assay

Apoptosis

Invasion and migration assay

High content and imaging

Multi-panel screening in parallel with fast turnaround time

Customized screening panel & tumor type specific panel in 96-well plate or 384-well plate format

Panel size ranges from a few lines to full panel

Diversified assay formats and technologies • Biochemical assays Luminescence, Fluorescent, TR-FRET, FRET, Mobility shift, LC/MS, Caliper, Absorbance• Radiometric assays Membrane based ligand binding, Enzymatic SPA, Flashplate, Filtration, Transporter uptake,• Cell-based target assays: AlphaScreen, ActivX, LANCE, Z’LITE, HTRF, Reporter gene assay (Luciferase, β-lac, GFP, β-gal), Stable

cell line generation, Primary cells & tissues• Mass Spectrometry based assays ADME, RapidFire/ADDA-MS/MS high throughput screening, biological assay development &

screening, metabolite profiling • High content, Flow cytometry & Multiplexing assays Cell signaling and transcription factor detection; Cell proliferation, cell

cycle, dies, Apoptosis and viability, Time-lapse migration, Nuclear translocation, Tube formation, Multiplexing biomarkers• Biophysics assay: thermal shift assay (SYPRO Orange dye), SPR (Biacore 8K)

Selectivity and specificity profiling • A variety of panels including kinase panel (~100 targets), epigenetic panel (7 HDACs), PDE panel (17 isoforms), GPCR panel

( ~120 targets and assays), Transporters (11 targets) • Focused safety panel (36 targets) with selected targets involved in multiple organ functions that are biologically critical

EXPERTISE AND KNOWLEDGE

Strict Quality Control and Assurance across Cell Panel Screen

Single Dose in Primary Screening IC50 confirmation Compound test in thermal shift assay

In vivo Pharmacology & Oncology Animal Models

Target validation and biomarkers

• Virus- and CRISPR-base target in vivo knockdown, knockout or over-expression technology

• Characterization of transgenic and GEM mice

• Biomarker discovery and assay development to determine and quantify various biomarker (IHC, IF, FISH, staining, etc.)

Various tumor models for PK/PD and efficacy evaluation

• Standard tumor models including subcutaneous Xenograft, Orthotopic, Metastatic, and murine Syngeneic tumor models

• Time and dose dependent PK/PD studies to establish PK and PD correlation

• In vivo efficacy to identify promising compounds and optimize lead candidates

Non GLP toxicology/safety and off-target assessment

• Dose range finding study

• Maximum tolerated dose (MTD) study

• Single and multiple dosing rodent toxicity

• Toxicokinetics and pathology

EXPERTISE AND KNOWLEDGE

Therapeutic Antibody Discovery

Oncology

Inflammation

Autoimmune disease

Neuroscience

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Proprietary phage libraries generate antibodies with full human sequences

• High quality human naive libraries with good size and high diversity

• Expertise in building custom designed and stable immune or non-immune antibody libraries

Phage-display technology with expertise on efficient and sophisticated antibody panning and screening

• Rich experience in diversified targets including soluble and cell surface antigens, peptide, aggregates, etc.

• Maturation technology to improve antibody affinity

Humanization of murine antibodies as therapeutic drug candidates

Excellent track record for strategic collaborations with big Pharma and Biotech

• Efficient delivery of over 500 unique antibody sequences on yearly basis

• Secured data storage and transfer for IP protection

• Multiple novel antibodies in preclinical development stage

HDB has developed considerable in vivo pharmacology expertise in oncology. Our team, consisting ofhighly experienced scientists with extensive biopharmaceutical and drug hunting expertise, supports invivo studies from target validation through candidate selection.

Affinity analysis with Biacore

Biomarkers detected with IHC methods which are located either in nucleus, cytoplasm or membrane of cancer cells and stroma.

HD Biosciences Shanghai (China)590 Ruiqing Rd, Zhangjiang Hi-Tech ParkShanghai 201201, P.R. ChinaTel: 86 (21) 5116-3700Fax: 86 (21) 5116-3766Email: info@hdbiosciences.com http://www.hdbiosciences.com

HD Biosciences is a Shanghai-based, biology-focused preclinical drug discovery contract researchorganization (CRO). The company offers comprehensive services around target validation, plate-based pharmacology, hit identification and lead discovery, therapeutic antibody discovery, in vivopharmacology, as well as other research and development services. The company currentlycollaborates with eight of the ten world’s largest pharmaceutical companies and has establishedstrategic partnership in many key R&D areas with impact to their portfolios. Strong scientificexpertise and high quality services allow us to consistently meet or exceed client expectations. Thishas earned the company a great reputation in the industry and has demonstrated its widelyrecognized leadership in preclinical contract research services.

HD Biosciences Lo Jolla (US)10355 Science Center Drive, Suite 260San Diego, CA 92121Tel: 01 (858) 888-7888Fax: 01 (858) 408-3317Email: info-lj@hdbiosciences.com http://www.hdbiosciences/HDB-LJ.com

Plate-basedPharmacology

(Assay & Screen)

Target Discovery & Validation

DMPK/Tox & In vivo Pharmacology

In vitro Pharmacology Platform

SAR Focused MedChem

Therapeutic Antibody Discovery & Biologics

IND Enabling & Risk Sharing Business

• Multi-lead optimization projects in parallel with aims to IND preclinical development

• Team up of SAR driven medicinal chemistry, in vitro pharmacology, DMPK/Tox, & animal models with therapeutic focuses

• Emphasis on scientific input, innovative technologies, efficient processes with seamless delivery & the quality that you can trust