about omics group - · pdf fileמחלקת ביוכימיה created date: 10/1/2014 4:23:40...
TRANSCRIPT
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About OMICS Group
Access Open of amalgamation an is International Group OMICS .events and conferences science international worldwide and publications
Established in the year 2007 with the sole aim of making the information on Sciences and technology ‘Open Access’, OMICS Group publishes 400 online
Engineering, Science, of aspects all in journals scholarly access openManagement and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also
where globe, the across annually conferences International 300 organizesknowledge transfer takes place through debates, round table discussions,
poster presentations, workshops, symposia and exhibitions.
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About OMICS Group Conferences
OMICS Group International is a pioneer and leading science event organizer, which publishes around 400 open access journals and conducts over 300 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit.
OMICS Group has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad,
Bengaluru and Mumbai.
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The role of oligosaccharides on structure and function of glycoprotein hormones: developing of agonists and antagonists
Prof. Fuad Fares University of Haifa
Proteomics
Chicago August 6th 2014
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Structure-Function studies Using site-directed mutagenesis
and gene transfer
Development of new analogs
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Therapeutical Recombinant proteins
1978 Human Growth Hormone 1979 Human Insulin
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The Problem
Cause adverse effects due to peak dose injection
Most therapeutic proteins are <30 kD and hence:
• Are filtered out quickly by the kidneys Are taken up by the liver and cleaved enzymatically
Have to be injected frequently for optimal therapy
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Success of Long-Lasting Proteins
PEGylation - Interferon α (SGP/Roche) PEGIntron/Pegasys $3.2 billion in sales in 2006
PEGylation - GCSF (Amgen) Neulasta $2.5 billion in sales in 2006
Hyper Glycosylation - EPO (Amgen) Aranesp (DNA Modifications) $3.9 billion in sales in 2006
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Structure-Function of Glycoprotein Hormones
FSH - Human Stimulating Hormone LH - Luteinizing Hormone
hCG - Human Chorionic Gonadotropin
TSH - Thyrotropin Hormone
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hCG hTSH
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Glycoprotein Hormone Subunits
α
hFSHβ
hLHβ hTSHβ
hCGβ
N N
N N
N
N
N N
O-linked
CTP
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D
B
C
A Two fertility hormones
hCG – maintains pregnancy and requires long T1/2
hLH – stimulates ovulation on a pulse mode requiring a short T1/2
Amino acid sequence of hCG & hLH is almost identical
The Technology was Created By Nature During Evolution - the CTP “cassette”
E The 28 amino acid C-terminal peptide (CTP) of hCG with its 4 O-glycans does not exist in hLH
hCG
hLH
CTP
T1/2 of hCG is ~5 times longer than T1/2 of LH
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SerSerSerSerLysAlaProProProSerLeuProSerProSerArgLeu
Pro GlyProSerAspThrProIleLeuProGln
O O
O
O
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Prediction of Folded and Unfolded Region of human chorionic gonadotropin (HCG) - chain B
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N-terminal
CTP not seen in structure
Crystal Structure of hGCβ showing long C-term lacking CTP
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The Role of CTP
Mutated hCGβ
N
N N
N
α
hCGβ
N N
N N
Stop Codon
TGA
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Deletion of CTP from hCG
- No effect on the assembly of subunits - No effect on receptor binding - No effect on in vitro bioactivity - Significantly decreased the bioactivity in vivo
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+
+
Protein CTP
Half- Life
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Designing New FSH Analog
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hFSHβ Gene
hCGβ Gene
CTP
CTP
hFSHβ Gene
Designing New FSH Analog
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NH2
NH2
α Exon 3 α Exon 4 α Exon 2 COOH
CTP FSHβ Exon 2 FSHβ Exon3 FSHβ Exon 1 COOH
hFSH - CTP
1- Assembly of the subunits 2- Binding to the receptor
3- In vitro Bioactivity 4- In vivo Bioactivity 5- Immunogenecity
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Gene Expression
CHO Transfection
α FSH β-CTP
Stable Clone
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hFSH-WT hFSH-CTP hFSH-(CTP)2
L M L M L M
Assembly of Subunits
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in vitro Studies
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Estr
ogen
(pg/
ml)
10 IU / 24h x 48h (IP)
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1 3 10 WT 4X
2.5IU
WT 1X
10 IU
C
0/4 0/4 0/4
3/3 4/4
4/4
Num
ber o
f ov
ulat
ed o
ocyt
es 0
10
30
20
40
50
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Half - Life
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SerSerSerSerLysAlaProProProSerLeuProSerProSerArgLeu
Pro GlyProSerAspThrProIleLeuProGln
O O
O
O
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Transfection into LDLD Cells
FSH -CTP
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Biological Activity
0
10
20
30
40
50
CHO Idl-D
E2 P
rodu
ctio
n (n
g/m
l)
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SerSerSerSerLysAlaProProProSerLeuProSerProSerArgLeu
Pro GlyProSerAspThrProIleLeuProGln
O
O O
O
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• FSH – CTP is effective in follicular stimulation
• FSH – CTP is safe
• FSH – CTP is not immunogenic
Organon - Merck
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February 2, 2010 — The European Commission (EC) has approved ELONVA (FSH-CTP)
Merck Receives Positive Regulatory Opinion for European Marketing of Long-Acting CTP-
Modified Fertility Treatment ELONVA
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FSH – CTP
(ELONVA)
World – Wide Use
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Start Up Company
“Enhancing the potency and longevity of highly valuable proteins”
CTP
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Start Up Company
Public Company
• NASDAQ, Stock Exchange, NY, USA.
• Tel-Aviv Stock Exchange, Tel-Aviv, Israel.
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OPKO Health, Inc. a multinational biopharmaceutical
and diagnostics company
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Designing Long Acting Proteins
Erythropoietin Growth Hormone Interferon Factors, XI & VII Short Peptides
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Erythropoietin (EPO)
The most common use is in people with anemia (low blood count) related to kidney dysfunction.
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N-term
C-term
3 - D Structure Analysis
Conclusion: Strands of both termini are fairly long and accessible.
Human Erythropoietin α (blue) with its Receptors (cyan)
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CTP EPO - cDNA CTP CTP
5’ - - 3’
TCCTCTTCC…..CTCCCACAATAA Ser Ser Ser …. Leu Pro Gln Term 118 119 120 …. 143 144 145
hCGβ-CTP
ATGGGGGTG….GGGGACAGA Met Gly Val….Gly Asp Arg 1 2 3 …. 190 191 192
EPO-cDNA
Xba I Not I
Human EPO-CTP3
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57
37
28
Human EPO-CTP3
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Hae
mat
ocrit
e
(cha
nge
from
bas
elin
e, %
)
40
30
20
10
Days
-10
0
10
20
30
40
1 5
Control rhEPO 3 x week
EPO-(CTP)3
rhEPO 1 x week
Human EPO-CTP3
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0.01
0.1
1
10
100
1000
10000
100000
0 50 100 150 200 250
E
E
A
rhEPO
EPO – (CTP)3
AARANESP
Time (hours)
Ery
thro
poie
tin (m
U/m
l)
Human EPO-CTP3
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Human Growth Hormone
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Pituitary
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Pharmaceutical and Biotechnological Uses of Growth Hormone
To treat children of pathologically short stature
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C-term
N-term
Conclusion: Both termini pointing away from the receptors and are accessible
3-D Structure Analysis
Human Growth Hormone (blue) with its Receptors (cyan)
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GH CTP
1 2 3 4
AgeI BamHI 5' '3
TCCTCTTCC…..CTCCCACAATAA Ser Ser Ser …. Leu Pro Gln Term 118 119 120 …. 143 144 145
ATGGGGGTG….GGGGACAGA Met Gly Val….Gly Asp Arg 1 2 3 …. 190 191 192
GH-cDNA CGβ-CTP
GH CTP CTP
CTP GH CTP CTP
GH CTP
GH CTP CTP
A.
B.
C.
D.
E.
Fig.1.
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Secretion of GH Analogs from CHO cells
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GH – (CTP)3
CTP GH CTP CTP
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0
100
200
300
400
500
0 20 40 60 80 100
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Half-life
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GH – (CTP)3
Expeiments in Rehsus Monkeys and human clinical trials phase I that GH-Long- acting is safe and not immunogenic
GH-(CTP)3 is in human clinical trials phase III
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Ligation of the CTP cassette gene bearing 4 O-linked Oligosaccharised chains to different proteins is an interesting strategy for increasing the in vivo half-life and in vivo bioactivity
This may allow reducing : A) Drug dose B) Number of injections
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TSH Studies
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hCG hTSH
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Hypothalamus
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TSH Subunits
α
N N
hTSHβ
N
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hTSH Variants
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hTSH Single Chain
hTSHβ Gene α Gene
N N N
hTSHβ α
hTSHβ Gene α Gene
N o o o o N N
hTSHβ α
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Expressed in CHO cells
Binds to TSH Receptor in high affinity as will as the TSH-WT
Biologically active
hTSH Single Chain
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hTSH – Single Chain Variants
hTSHβ Gene α Gene
hTSHβ α
hTSHβ Gene α Gene
N o o o o
hTSHβ α
o o o o
α
N N
hTSHβ
N
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Secretion of TSH variants
48K 38K
25K
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Receptor Binding TSH (Mutants)
TSH variants (µu/ml)
value variant
200 hTSH dimer WT
18 hTSHβCTPα1+2
100 hTSHβCTPα(deg)
IC50(µU/ml)
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hTSH (µU/ml)
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TSH Antagonist
hTSH(50µu/ml)+hTSH variants (µu/ml)
cAM
P(pm
ol/w
ell)
hTSH(50µu/ml)+hTSH variants (µU/ml)
T3 (f
mol
/wel
l)
hTSH(50mu/ml)+hTSH variants (µU/ml)
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Thyroid Stimulating Immunoglobolins
(TSI)
Graves’ Disease
TSH Receptor
Hyperthyroidism
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TSI Antagonist
hTSI+βCTPα1+2
hTSI (0.75µu/ml)+hTSH variants (µu/ml)
hTSI+βCTPα(deg)
hTSI (0.75µu/ml)+hTSH variants (µu/ml)
cAM
P(pm
ol/w
ell)
hTSI+βCTPα1+2
hTSI+βCTPα(deg)
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Cell membrane
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Deletion of the N-linked oligosaccharides from TSH resulted in partial antagonists of TSH and TSI at the level of the receptor binding site.
TSH variants may offer a novel
therapeutic strategy in the treatment of
hyperthyroidism and Graves’ disease.
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Prof. Zaki Kraiem Prof. Irving Boime Prof. Aaron Hsueh
Dr. Naeil Azam Dr. Avri Havron Orit Sadeh Dr. Eyal Fima Flonia Levi Rinat Alenberg Mr. Shai Novik
Dr. Sharif Ganim Dr.Taleb Hajoj
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Clinical Advisory Panels World Known Opinion Leaders
hGH Ron Rosenfeld, MD, Stanford Barry Sherman, MD, Genentech, BiPar Zvi Zadik, MD, Hebrew University
EPO Allen Nissenson, MD, UCLA Anatole Besarab, MD, Henry Ford, Detroit
Interferon-beta William Mobley, MD, Stanford Hillel Panitch, MD, Vermont Ron Milo, MD, Israel
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• National Institutes of Health (NIH)
•The Rockefeller Foundation
•United States - Israel Binational Science Foundation (BSF) • Israel Science Foundation (ISF)
• The Israel Ministry of Science • The Israel Ministry of Industry and Trade
•Private Investors
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