Biological-lecture 2-2022-23.pdf

2/22/2023
Biological Products By: Sintayehu A.
1
Growth Hormone

Growth Hormone…
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 Human growth hormone (hGH) is a protein hormone
essential for normal growth and development in
humans
 GH is secreted by pituitary gland
 absence or inadequate GH during childhood results
in dwarfism
 too much GH causes acromegaly, a form of
gigantism

Growth Hormone…
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 Naturally occurring hGH has been replaced with
rDNA products
 rhGH is produced in E. coli
 Some of rhGH preparations approved for general
medical use are:
 Humatrope: indicated for treatment of hGH
deficiency in children

Growth Hormone…
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 Somatropin: indicated for the long-term treatment of
children
 who fail to grow and
 for growth problems associated with CRF
 Somavert: GH receptor antagonist
 indicated for treatment of patients suffering from
acromegaly
 Somatostatin: indicated for treatment of acromegaly

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Gonadotrophins

Gonadotrophins
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 The three hormones collectively called gonadotrophins
are
 Luteinizing hormone (LH)
 follicle-stimulating hormone (FSH)
 human chorionic gonadotropin (hCG)
their primary target is the gonads
regulate reproductive function

Gonadotrophins…
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 Most gonadotrophins are synthesized by the pituitary
glands
insufficient endogenous production adversely
affect reproductive function
treated by administration of an exogenous
preparation

Gonadotrophins…
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Recombinant gonadotrophins
 Gonadotrophins are now also produced by rDNA
technology
 available recombinant forms are
rFSH (follitropin-alfa and follitropin-beta)
rLH (lutropin-alfa), and
rhCG (choriogonadotropin-alfa)

Gonadotrophins…
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Recombinant gonadotrophins …
Follitropins
hormonal products that consist entirely of FSH
used to stimulate ovarian follicle growth in women
are human FSH preparations produced by rDNA

Gonadotrophins…
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 Follitropin-alfa ( or Gonal-F and follitropin-beta (or
Follistim)
 both are approved for infertility treatment
Lutropin alfa (Luveris)
 rDNA product of human LH
 It is indicated for use in infertile women

Gonadotrophins…
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Ovitrelle (choriogonadotropin-alfa)
 It is a recombinant hCG (rhCG)
 It is indicated for the treatment of female infertility
due to anovulation

Other recombinant hormones
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Oxytocin and vasopressin
 Oxytocin: has uterotonic action and plays role in milk
ejection
 Exogenous oxytocin most commonly is used for
induction of labor

Other recombinant hormones…
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 Vasopressin: Human vasopressin is chemically very
similar to oxytocin
 Its physiologic role is
 regulation of water reabsorption in the renal
tubules
antidiuretic hormone (ADH)
 An inadequate ADH can cause diabetes insipidus
 Desmopressin : ???

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Recombinant blood products

Recombinant blood products…
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 Blood and blood products constitute a major group of
traditional biologics
 The main components of blood are the red and white
blood cells, along with platelets
 Whole blood, red blood cell and platelet concentrates
remains in routine therapeutic use

Recombinant blood products…
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 A variety of therapeutically important blood proteins also
purified from plasma
 These include various clotting factors and immunoglobulins
 Blood proteins/blood-related proteins produced by genetic
engineering include
 recombinant coagulation factors, anticoagulants and
thrombolytic

Clotting factors
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 Blood plays various vital roles within the body
 blood loss occurs upon vascular damage
 Thus, the rapid arrest of blood loss is very important
to maintain a relatively constant blood volume
effectively maintaining haemostasis

Clotting factors …
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 In humans, three main mechanisms underline the
haemostatic process
 Clumping of blood platelets at the site of vascular
injury
 Localized constriction of the blood vessel
 Induction of the blood coagulation cascade
 Fibrinogen converted into fibrin
 Fibrin aggregate at the site of damage, thus
forming a clot (thrombus) to seal it off

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 The coagulation cascade involves a series of
enzymatic processes and protein activations
transform inactive pro-enzymes to their active
forms
result in formation of thrombin
 These enzymes are known as blood-clotting factors

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 Blood coagulation is thus, dependent upon clotting
factors and platelets
 More than 12 blood-clotting factors, including factors
VII, VIII, IX, and X are pivotal to the formation of
thrombin

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 Factor X converts prothrombin into thrombin
 Thrombin converts inactive fibrinogen to fibrin
 Fibrin:
 Individual fibrin molecules aggregate to form clot
 deposits at the injury site reduce leakage

Clotting disorders
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 Genetic defects of any clotting factor can have serious clinical
consequences
 In order to promote effective clotting, the coagulation
pathways must be functional
 inhibition of these pathways will result in severely retarded
coagulation ability
 spontaneous bruising and haemorrhage

Clotting disorders…
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Hemophilias
 The hemophilias are a group of related, usually inherited,
bleeding disorders
 Inherited bleeding disorders include abnormalities of
coagulation factors as well as platelet function

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 Abnormalities that result in a delay in blood
coagulation
 Types:
Hemophilia A
Hemophilia B
 Hemophilia A: a lifelong bleeding disorder, results
from a deficiency of factor VIII
 Treatment: Antihemophiliac factor, or factor VIII

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 Haemophilia B : clotting disorders resulted from
deficiency of factor IX
 Haemophilia B are treated by i.v. administration of a
concentrate of factor IX
 obtained by fractionation of human blood

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 However, administration of whole blood or concentrates
of the relevant coagulation factor purified from whole
blood entails significant risk ???
 This has hastened the development of recombinant
products
recombinant coagulation factors

Recombinant blood products
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Some recombinant blood coagulation factors
Product name Indication
rhFactor VIII( Advate) Haemophilia A
rhFactor VIII (Bioclate) Haemophilia A
rhFactor IX (Benefix) Haemophilia B
rhFactor VIII (Kogenate) Haemophilia A
rhFactor VIII (Recombinate) Haemophilia A
rhFactor VIIa (NovoSeven) Haemophilia A and B

Anticoagulants
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 inappropriate clotting can give rise to serious,
sometimes fatal medical conditions
 clot (a thrombus) within diseased blood vessels
partially or completely obstructs the flow of blood
 Anticoagulants are substances that can prevent blood
from clotting

Anticoagulants…
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 The major anticoagulants used for therapeutic
purposes are
 Heparin
 Warfarin
 Hirudin
 Ancrod

Anticoagulants…
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Heparin
 mainly found stored intra-cellularly in mast cells
 Upon release into the bloodstream, it binds to and
activates anti-thrombin
 heparin–anti-thrombin complex then binds a number
of activated clotting factors (i.e. IIa, IXa, Xa, XIa and
XIIa)
inactivating activated clotting factors

Anticoagulants…
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 Heparin was originally extracted from liver (hence its
name)
 commercial preparations are extracted from beef
lung or porcine gastric mucosa

Anticoagulants…
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Hirudin
 Hirudin is a leech-derived anticoagulant that
functions by directly inhibiting thrombin
 Two hirudin derivatives are available as inhibitors of
thrombin for clinical use
lepirudin (Refludan)
bivalrudin (Angiomax)

Anticoagulants…
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 The hirudin gene has been expressed in a number of
recombinant systems (E. coli, B. subtilis and S.
cerevisiae)

Thrombolytic agents
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 Deposition of fibrin and platelets in the vasculature
leads to thromboembolic diseases
mortality and morbidity
 clot is removed via an enzymatic degradative process
known as fibrinolysis
 During fibrinolysis,
plasminogen is enzymatically converted to the
plasmin
plasmin digests the insoluble fibrin matrix to
soluble fibrin degradation products

Thrombolytic agents…
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Tissue plasminogen activator (t-PA)
 t-PA (aka fibrinokinase) represents the most important
physiological activator of plasminogen
t-PA
Plasminogen
Fibrin
Plasmin
Fibrin
degradation
products

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Recombinant Thrombolytic Agents: rt-PA
 t-PA normally synthesized at low quantities
 The t-PA gene was cloned from the melanoma cell line
 this facilitated subsequent large-scale production in
CHO cell lines by rDNA technology
 Alteplase: the first rDNA thrombolytic agents
effective in the early treatment of patients with
AMI
 Streptokinase???

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Urokinase
 Urokinase is produced by kidney
 It is found both in the plasma and urine
 It is capable of converting plasminogen into
plasmin
 Urokinase utilized medically is generally purified
directly from human urine
 It can also be produced by rDNA technology

Biological-lecture 2-2022-23.pdf

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Biological-lecture 2-2022-23.pdf