疫苗與新藥開發 ( 2 )
Vaccine and Drug Development
Common Diseases in the 21st Century
24 September, 2015
南臺科技大學-生物科技系
（碩研生技一）
蘇益仁 教授
二十世紀和二十一世紀人類文明的差異
•
•
•
•
由飢餓到過度營養
由農業生活到工業時代以迄資訊電腦化時代
飲食由自然食品演變到精緻化
人類疾病由營養不良及傳染病演變到中風,心肌
梗塞,肥胖及癌症
• 藥物的研發也由維他命營養補充品,抗生素演變
為心臟血管藥物及抗癌藥物
• 二十一世紀新起樂活的理念使人類文明回復到
二十世紀前比較悠閒及健康的生活
• 中國文明養生的概念也再度受到醫學界的重
視—herbal medicine
臺灣的十大死因
suicide
2.82%
others
24.23%
liver disase and
liver cirrhosis
3.70%
pneumonia
4.23%
cardiopathy
9.33%
metabolic syndrome,
30.98%
Cerebral vascular
disease
9.24%
diabetes
7.34%
accident
5.12%
cancer
28.92%
nephritis and other
relativity disease
3.66%
hypertension
1.42%
★ Metabolic syndrome related disease and cancers occupied the majority
of the top 10 causes of death
 Infectious diseases represent the major causes before 20th century, but decreases
in the 21st century, except for HIV, TB, malaria, dengue--. But, SARS, Ebola,
Influenza outbreak cause high mortality and social social panic.
二十一世紀主要疾病皆與營養及代謝症候群有關
人類演化史
糖尿病
動脈粥狀硬化
高血脂
葡萄糖耐受性受損
高血壓
胰島素抗性
凝血功能降低
肥胖
高胰島素血症
尿酸過高
代謝症候群與多種疾病相關，
因此也稱為X 症候群(syndrome X)
多囊性卵巢症
候群
excess food intake,
less exercise
Genetic defects
Meta
bolic
syndr
ome
physical inactivity
Good
cytokine
脂肪在內臟堆積
Bad
cytokine
TNF-α, FFA, leptin
Insulin resistance
hyperglycemia
男性腰圍大於90公分
女性腰圍大於80公分
FFA 
TG、HDL-cholesterol
Hyperlipidaemia
adiponectin
Angiotensin
HDL-cholesterol
PAI-1
hypertension
atherosclerosis
NO
treatment
Diabetes and other related disease
stroke、myocardial infarction and
other related disease
動脈硬化的演變過程—myocardial infarct
and stroke
Etiology of Cancers: Carcinogenic Agents
• Chemical carcinogens：
Direct-acting carcinogens
Natural products：Betel nuts, aflatoxin, smoking
• Radiation carcinogenesis：
Ionizing radiation：chromosome breakage, translocation,
mutation
UV ray：pyrimidine dimer, leading to mutation
• Viral and microbial carcinogens：
DNA viruses
RNA viruses
Helicobacter pylori
• Hereditary cancers：
Xeroderma pigmentosa
Retinoblastoma (Rb)
Colon, breast, ---et al
Genetic model for colorectal carcinogenesis
Kinetics of tumorigenesis: Tumor development
usually takes a long period, a balance between
tumor cells and environment factors
Different Kinds of Cancer
Some common
carcinomas:
Lung
Breast (women)
Colon
Bladder
Prostate
(men)
Leukemias:
Bloodstream
Lymphomas:
Lymph nodes
Some common
sarcomas:
Fat
Bone
Muscle
Betel nut-associated oral cancer
Arsenic skin cancer in Southwestern Taiwan:
Multiple at different stages
脂肪肝會增加罹患肝癌的危險達2.5至3倍
(1) Non-alcoholic
fatty liver to HCC;
(2) HCV HCC
(3) HBV HCC
Cancer
Science 332(24), p1519, 2011
肝癌是國病，疫苗已可控制B型肝炎病毒感染
ΔS1(A181), 19M
ΔS2(A205), 24M
B型肝炎病毒引起肝癌一個分子機制，提供藥物
開發的方向
ER
pre-S Mutants
5
1
PreS1+PreS2
PreS2
ER stress dependent
ER stress independent
JAB1
pp38
VEGF
p27
6
Cdk2
NF-kB
3
Akt
COX-2
Rb
mTOR
Cyclin A
Ca2+
2
ROI
Oxidative DNA
damages
4
Hepatocyte
proliferation
Genomic
instability
1 Wang HC et al., 2003
2
Hsieh YH et al., 2004
3
Hung JH et al., 2004
4
Wang HC et al., 2005
5
Hsieh YH et al., 2007
6
Yang JC et al., 2009
HCC
好發在臺灣的EB病毒相關T細胞淋巴癌
Childhood HLH
T or NK/T lymphoma
EBV感染T細胞並演變成T細胞淋巴癌的過程
Clinical S/S
Hemophagocytic syndrome
T and Mψ activation
Proinflammatory cytokines
EBV
T
T
Primary EBV
infection
Molecular
events
LMP-1
NFkB
ATF5↑
Sustained
Cell proliferation
T
Chronic active
EBV infection
NFkB activation:
Growth factors↑
Anti-apoptotic ↑
COX-2, MMP ↑
Genomic
instability
EBV + T (NK/T)
Cell lymphoma
T
Chromosome abnormalities:
6q25
C-kit
9p21
ERK, Akt↑
Therapy
Anti-virals
Immunomodulation
NFkB inhibitors
PPAR agonists
Chemotherapy
NFkB inhibitors
PPAR agonists
Emerging / re-emerging infectious
diseases,1996–2014
Legionnaire’s Disease
Cryptosporidiosis
E.coli O157
BSE
Human Monkepox
Multidrug resistant
Salmonella
E.coli non-O157
Typhoid
Malaria
E.coli O157
nvCJD
Lyme Borreliosis
West Nile Virus
Reston virus
Lassa fever
Yellow fever
Venezuelan
Equine Encephalitis
Dengue
haemhorrhagic
fever
Diphtheria
West Nile
Fever
Echinococcosis
Buruli ulcer
Ebola
haemorrhagic
fever
Cholera
Cholera 0139
RVF/VHF
O’nyongnyong fever
Severe Acute
Respiratory Syndrome
Influenza
(SARS) A(H5N1;
H7N9); EV71
Nipah Virus
Reston Virus
Dengue
haemhorrhagic
fever
Human
Monkeypox
Cholera
Hendra virus
Ross River
virus
Ebola virus epidemic in West Africa
Date
Situation map of the outbreak
December 2013-present
HIV: current prevalence
and recent changes, 1996–2010
+ 1 300%
+
20%
+ 20%
+ 100%
Adult prevalence rate
15.0% – 36.0%
5.0a% – 15.0%
1.0% – 5.0%
0.5% – 1.0%
0.1% – 0.5%
0.0% – 0.1%
not available
+ 160%
+
60%
+ 40%
+ 30%
+ 20%
Epidemic dengue haemorrhagic fever in Asia
since 1950, countries reporting to WHO
1950-1969
1970-1979
1980>
流感新病毒的產生
Garten, R. J et al., 2009. Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses
Circulating in Humans. Science.
抗病毒藥物對流感有效

Neuraminidase inhibitors
effective in preventing serious clinical disease if used
early in infection (both A and B)
role in prophylaxis to prevent epidemic spread
unknown

M2 – Inhibitors
effective in preventing serious clinical
disease if used early in infection (A only)
resistance/side effects probably make
unsatisfactory for prophylaxis
流感疫苗研發是重要生技產業發展
Government policy to spend 1.3 billions
to support the development of flu vaccine
plant in Taiwan
Emergency production in NHRI pilot plant
to provide 100,000-dosages for the
priority group—medical staffs and flu
controller
腸病毒感染的臨床表徵
Clinical presentations of Enteroviruses
1. Infection of EV can cause hand-footand-mouth disease (HFMD), aseptic
meningitis, myocarditis, hepatitis,
acute flaccid paralysis (AFP),
brainstem encephalitis, and
pulmonary edema.
2. EV71 is uniquely associated with
brainstem encephalitis and
pulmonary edema.
腸病毒的基因結構及種類
Enterovirus – gene structure
Picornaviridae, 7.5kb ssRNA
Four species: A,B,C,D
P1: Antigenicity
P2: Replication, virulence
登革熱與氣候及蚊子傳遞有關
•
•
•
•
Transmission: Aedes mosquitoes
Incubation period: 2-7 days
Infectious period: <7 days
Immune response
– Long-lasting immunity to infecting serotype;
transient cross-immunity to all four serotypes
Ab-dependent enhancement (ADE)
– humoral and cellular
臺灣登革熱流行與北回歸線有關
Aedes albopictus
Below sea level
1500 m
Aedes albopictus
Susceptible
hosts
Eggs
Aedes aegypti
Aedes albopictus
Susceptible
hosts
Eggs
Aedes aegypti
2003-2004 Aedes
aegypti distribution
Aedes aeyypti
collected before
結核病仍是臺灣及世界上重要的疾病
Mycobacterium tuberculosis
臺灣結核病的年齡分布
350
Multivariate
Rate ( per 100K)
300
250
200
150
Male gender
Age (per 1 yr)
Diabetes
COPD
Hypertension
Chronic kidney disease
HR
P value
2.759
1.042
1.246
1.464
0.785
1.212
<0.001
<0.001
0.001
<0.001
<0.001
0.005
95% CI
2.525
1.036
1.099
1.223
0.717
1.000
3.014
1.047
1.412
1.752
0.859
1.468
2005
2006
2007
2008
2009
2010
100
50
0
0-4
5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 ≧65
Age group (years)
Data from TCDC
Data from National Health Insurance Database
疫苗產業─臺灣前十大疫苗產品
全部藥
品排名
商品名
適應症
廠商
2012年
成長率
銷售額
37
Prevenarr 13
肺炎鏈球菌疫苗
Pfizer
56,154
117.8
171
Gardasil
子宮頸癌疫苗
Merck
16,253
7.5
240
RotaTeq
輪狀病毒疫苗
MSD
10,986
71.1
250
Rotarix
輪狀病毒疫苗
GSK
10,552
14.4
342
Cervaris™ 16/18
子宮頸癌疫苗
GSK
7,058
69.4
439
Prevenar
肺炎鏈球菌疫苗
Pfizer
5,264
-62.4
555
BCG
Immunotherapeutic
Immucyst
BCG 免疫治療劑
Sanofi
Aventis
3,951
-21.3
557
Engerix-B
B型肝炎疫苗
GSK
3,930
-9.5
587
Synflorix™
肺炎鏈球菌疫苗
GSK
3,723
-40.6
617
Adacel
三合一補追疫苗
Sanofi
Aventis
3,437
72.4
癌症藥物開發的策略
1. More selective anti-cancer drugs with less toxicities
2. Decrease the toxicity of current cancer treatment
modalities without compromising their anti-cancer
activity
“Reductive” single chemical approach could make
incremental improvement in most cases
“Holistic” polychemical approach should be
entertained
生技藥物開發平台的建立
Biological Function
Monitoring
100
3.0
50
1.5
0
0.0
90
0
72
0
Ma
s
54
0
a.m
3
.u.) 60
PPARs activities (Reporter assay)
mTOR inhibition (Western blot)
Intensity (log)
Absorbance (%)
Component Fingerprint
HPLC/GC-MS
32
s(
28
24
18
0
20
16
ntion
Rete
Time
)
(min
Stability
Animal Toxicology
(Safety)
Human/Animal Studies
(Efficacy)
37