Developing long acting agonists and antagonists of glycoprotein hormones using gene fusion and gene transfer: from bench to clinics Prof. Fuad Fares Prof. Fuad Fares University of Haifa University of Haifa 2 nd International conference on Endocrinology Chicago October 2014
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Developing long acting agonists and antagonists of glycoprotein hormones using gene fusion and gene transfer: from bench to clinics Prof. Fuad Fares Prof.
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Developing long acting agonists and antagonists of glycoprotein hormones using gene fusion and gene transfer:
from bench to clinics
Prof. Fuad FaresProf. Fuad FaresUniversity of HaifaUniversity of Haifa
2nd International conference on EndocrinologyChicago
1978 Human Growth 1978 Human Growth HormoneHormone
1979 Human Insulin1979 Human Insulin
The ProblemThe Problem
Cause adverse effects due to Cause adverse effects due to peak dose injectionpeak dose injection
Most therapeutic proteins are <30 Most therapeutic proteins are <30 kD and hencekD and hence::
• Are filtered out quickly by the kidneysAre filtered out quickly by the kidneys Are taken up by the liver and cleaved enzymaticallyAre taken up by the liver and cleaved enzymatically
Have to be injected frequently for optimal therapyHave to be injected frequently for optimal therapy
Success of Long-Lasting Success of Long-Lasting ProteinsProteins
PEGylationPEGylation - Interferon - Interferon (SGP/Roche)(SGP/Roche) PEGIntron/PegasysPEGIntron/Pegasys $3.2 billion in sales in 2006$3.2 billion in sales in 2006
PEGylationPEGylation - GCSF (Amgen) - GCSF (Amgen) NeulastaNeulasta $2.5 billion in sales in 2006 $2.5 billion in sales in 2006
Hyper Glycosylation Hyper Glycosylation - EPO - EPO (Amgen)(Amgen) Aranesp (DNA Modifications) Aranesp (DNA Modifications) $3.9 billion in sales in 2006 $3.9 billion in sales in 2006
Structure-Function of Structure-Function of Glycoprotein HormonesGlycoprotein Hormones
FSH FSH - Human Stimulating Hormone- Human Stimulating Hormone LHLH - Luteinizing Hormone - Luteinizing Hormone
hCGhCG - Human Chorionic Gonadotropin - Human Chorionic Gonadotropin
Expeiments in Rehsus Monkeys Expeiments in Rehsus Monkeys and human clinical trials phase and human clinical trials phase I that GH-Long- acting is safe I that GH-Long- acting is safe and and not immunogenicnot immunogenic
GH-(CTP)3 is in human GH-(CTP)3 is in human clinical trials phase IIIclinical trials phase III
ConclusionsConclusions
Ligation of the CTP cassette geneLigation of the CTP cassette gene bearing 4 O-linked bearing 4 O-linked Oligosaccharised chains to Oligosaccharised chains to different proteins is an interesting different proteins is an interesting strategy for increasing the strategy for increasing the in vivoin vivo half-life and half-life and in vivoin vivo bioactivity bioactivity
This may allow reducing: A) Drug dose
B) Number of injections
TSH StudiesTSH Studies
hCG hTSH
Thyroid
Peripheral tissue
Pituitary
TSH
T3T4
HypothalamusTRH
TSH Subunits
N N
hTSH N
- WT NH2 ....... Asn -X-Thr...... Asn-X-Thr...
CHO CHO
52 78
- 1 NH2 ....... Asp -X-Thr...... Asn-X-Thr...
CHO
52 78
-2 NH2 ....... Asn -X-Thr...... Asp-X-Thr...
CHO
-1+2 NH2 ....... Asp-X-Thr...... Asp-X-Thr...
52 78
TSH - WT NH2 ...... Asn-X-Thr......
CHO
52 78
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hTSH Variants
hTSH Single ChainhTSH Single Chain
hTSH Gene Gene
N N N
hTSH
hTSH Gene Gene CTP
N o o o o N N
hTSHCTP
Expressed in CHO cells
Binds to TSH Receptor in high affinity as will as the TSH-WT
Biologically active
hTSH Single Chain
hTSH hTSH –– Single Chain Single Chain VariantsVariants
hTSH Gene Gene CTP
hTSHCTPdeg
hTSH Gene Gene CTP
N o o o o
hTSHCTP1+2
o o o o
N N
hTSH
N
Secretion of TSH variantsSecretion of TSH variants
ConclusionsConclusions 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 TSH variants may offer a novel
therapeutic strategy in the treatment oftherapeutic strategy in the treatment of
hyperthyroidism and Graves’ disease.hyperthyroidism and Graves’ disease.
Prof. Zaki Kraiem Prof. Irving Boime
Prof. Aaron Hsueh
Dr. Naeil Azam Dr. Avri Havron Orit Sadeh Dr. Eyal FimaFlonia LeviRinat Alenberg Mr. Shai Novik
Dr. Sharif GanimDr.Taleb Hajoj
Clinical Advisory PanelsClinical Advisory PanelsWorld Known Opinion World Known Opinion
LeadersLeaders hGHhGH
Ron Rosenfeld, MD, StanfordRon Rosenfeld, MD, Stanford Barry Sherman, MD, Genentech, BiParBarry Sherman, MD, Genentech, BiPar Zvi Zadik, MD, Hebrew UniversityZvi Zadik, MD, Hebrew University
EPOEPO Allen Nissenson, MD, UCLAAllen Nissenson, MD, UCLA Anatole Besarab, MD, Henry Ford, DetroitAnatole Besarab, MD, Henry Ford, Detroit
Interferon-betaInterferon-beta William Mobley, MD, StanfordWilliam Mobley, MD, Stanford Hillel Panitch, MD, VermontHillel Panitch, MD, Vermont Ron Milo, MD, IsraelRon Milo, MD, Israel
• 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