Biological treatment - principles,
technology, examples
Biological drug
• „Biodrugs, biologics, targeted treatment “
Recombinant proteins, peptides,
antibodies, hormones
substances derived from blood / plasma and recombination variants
• „Biologicals, Biopharmacy,
Biopharmaceuticals“
- recombinant proteins, peptides,
antibodies, hormones
+ Stem cells, xenotransplantation, gene and
antisense therapy
Biological drugs
• designed to specifically target a biological
phenomenon, gene, protein, or group of
genes or proteins thought to be involved in
the disease.
Traditional/Classical vs. Biological drug
large, complex molecules, commonly
proteins> 50 kDa
manufactured using living organisms
/ cells
- risk contamination
- own "inherited„ activity
Complex heterogeneous structure
matrix from which was drug isolated
More difficult to characterize
(3D conformation)
mechanism of action is complex,
sometimes not fully understood
Usually immunogenic
Mostly without interaction at P450
Small molecule <1kDa
Production of chemical synthesis
/ isolation of plant
Less critical steps in the synthesis
Very well characterized
Molecular mechanism of action
usually better described
Linear dose-response
relationship
Mostly non-immunogenic
Usually with pharmacokinetic
interactions at P450
Often very similar / identical with
the molecules of the human
body.
Usually targeting the center of
disease/anormality.
Can be used to treat previously
difficult-to-treat diseases.
The difficult adjustment to DDF
Often a small molecule, different
from endogenous substances
Expose its effects throughout the
whole body
Limited efficacy for some states
Easy handling and formulation of
DDF
Traditional/Classical vs. Biological drug
Research and development of
Biological drugs
• The development of biologics is 10 - 15 years, costs 1.5
billion USD
• Biologics are produced by the genetically modified
host cells (bacterial, yeast, mammalian and plant) into
which was inserted the genetic information stored in
DNA.
• The first drug produced by biotechnological procedure
was insulin (in 1978, registering 1982).
• The discovery of biotechnological production of
pharmaceuticals, respectively. monoclonal antibodies,
was in 1984 awarded the Nobel Prize.
Targeted effects of biologicals
• A specific effect of biologics is targeted - a
specific target structure, antigen, enzyme,
signal path (e.g. tumor cells).
• Biologics are able to identify the damaged cells
for destruction by the immune system.
• Can prevent the growth and proliferation of
cells that cause disease.
• Can deliver drug directly to the target which
increases the effectiveness of treatment.
History
• 1972 - obtained recombinant deoxyribonucleic
acid (rDNA)
• 1975 - first monoclonal antibody (MAb).
• This was followed by the establishment of the first
biotech
pharmaceutical companies. USA - Genentech
Europe - Biotech
• 1982 - The first biotech product was - recombinant
insulin (Genentech, marketed by Eli Lilly)
• 1986 monoclonal antibody OKT3 (OrthoCloneR)
recombination. IFN
Examples of Biological drugs
1) Imunomodulating biologics
MAb (Infliximab) and fusion proteins (etanercept), IFN
2) Hormones – insulin, GH
3) Vaccines – e.g. HVB, HPV
4) Growth factors – erytropoetin, trombopoetin, CSF
5) Enzymes for the treatment of hereditary diseases
(monogenic) (e.g. Imiglucerase for the treatment of Gaucher
disease)
6) Biologics influencing homeostasis- f. VII, F VIII, F IX, other inh.
Of coaglation or activators of fibrinolysis
7) Gene therapy (e.g.. Alipogen tiparvovek – LPL gene)
Advantages for the patients
• Better efficiency vs. "Classical" drugs
• Biologicals are used under the supervision of experts in
specialized centers.
• targeted, personalized treatment, which is always
personalized
• the patient undergoes a more detailed examination before
medication
• better understanding of the basic properties of the drug and
its effects
• better solution of possible ADRs, their early detection
Risks and disadvantages of biological
drugs in general
• carcinogenicity
• allergenic potential
• contaminants from the source cells
• stabilizing additives (cryopreservation stabilizers)
• sterility
• stability, variability of drugs (biotechnology products)
• adverse effects - dead teenager in first stage CT - liver
toxicity after gene therapy of congenital deficiency of
the enzyme using an adenoviral vector (1999)
Nomenlature
• Derived from biochemical name (Pegasys -PEG
IFN)
• The name given by the manufacturer unrelated
to the effect of the origin
• Hormone with different tradename (Serostim,
Saizen, Zorbtive)
• MAB- system root words and suffixes
Nomenclature of MAB
• Generally: suffix -mab
• Letter before suffix:
– o – of mice origin
– a - rat origin
– e - hamster origin
– i - of primates
– u – of human origin (human cell line production)
– zu – humanized
– xi - chimeric
Mouse MAb
100% of the mice
orig.
Hypersensitivity
High levels of Ab
(not used clinically)
Human MAb
100% human
Hypersensitivity
Low levels of
Neutralizing
Antibodies
(panitumumab
adalimumab)
Humanized
5-10% mice orig.
MAb
Hypersensitivity
Low levels of
Neutralizing
Antibodies
(Trastuzumab
Certolizumab)
Chimeric MAb
34% of mice orig.
Hypersensitivity
Low levels of
circulating Ab
(rituximab
infliximab)
Nomenclature of MAB
Sometimes encoding indication
• lim - immune
• bac - bacterial
• cir- cardiovascular
• tu - malignity
E.g. rituximab - chimeric MAB to treat Non-Hodgkin.
lymphomas
alemtuzumab - humanized antibody to the CD52 glycoprotein
CLL
Production of biological drugs
Isolation from natural sources - historically:
• insulin from the pancreas of cattle, pigs
(recombinant today)
• h-choriogonadotropin - from the urine of pregnant
women (today recombinant)
• hirudin - Medical leeches (H. officinalis) (today
synthetic / recombinant)
The production of biological
drugs - recombinant technology
• DNA extraction
• product / synthesis according to library
• transformation / DNA transfection into producer
cells
• production
• purification
• stabilization
• testing (biological activity - CT I-III)
• registration ( RCT + IV )
The production of biological
drugs - recombinant technology
• DNA extraction
• product / synthesis according to library
• transformation / DNA transfection into producer
cells
• production
• purification
• stabilization
• testing (biological activity - CT I-III)
• registration ( RCT + IV )
Transformation/transfection with use of
plasmid start of replication
marker of selection
polycloning site (enables insertion of DNA of
foreign origin)
transcription promoter and terminator
selection
The production of biological drugs
- recombinant technology
• production microorganisms
- bacteria
- yeast
• Tissue cultures of higher organisms
• Cell-free expression systems
• Genetically modified animals, plants
The production of biological drugs recombinant
technology
• Production by microorganisms
- Bacteria - optimized E. coli strains (mutations of
periplasmatic and membrane protease)
- Yeasts - S. cerevisiae - Pichia pastoris ?
The production of biological drugs recombinant
technology
E. Coli
- The synthesis of proteins without posttranslational modifications
- Cheap medium, mutated forms of E. coli with advantageous
properties - increase the stability of the gene product ...
- Modification of wall, transformation of plasmid (DNA product
introduction) - thermal shock, electroporation
- Selection - resistance to antibiotics / cell culture media
- Production of the peptide together with peptide sequences which
ensure binding to an affinity carrier
- Renaturation
- E.g. IFN , GSM, insulin, growth hormone ...
The production of biological drugs recombinant
technology
S. Cerevisieae
- suitable for the synthesis of proteins with posttranslational
modifications
- Haploid yeast - the possibility of hybridization
- Easy , economical cultivation generation time of 2h
- GRAS - " Generally regarded as safe"
- Mutants with advantageous properties - increase the stability of
the gene product ...
The production of biological drugs recombinant
technology
S. cerevisieae
- modification of cell wall, transformation of plasmid (various
vectors)
- selection - auxotrophic strains (disabled biosynthetic pathway for
AA, NA); plasmid introduce this gene – only transformed yeast are
viable in selection media (ATB)
- production of the peptide together with peptide sequences which
ensure binding to an affinity carrier
- renaturation
- E.g. insulin, growth hormone ...
The production of biological drugs recombinant
technology
Pichia pastoris
- higher genet. stability, possibility of similar glycosylation of
proteins as in humans
The production of biological drugs recombinant
technology
Tissue cultures of higher organisms
- About 60% of recombinant proteins
positives: same way of modifications as in humans
a wide variety of products
eliminates ethical / technical problems
(isolation, animal cells, the lack of material)
negatives: higher risk of contamination
(rich medium, slower growth, expensive,
difficult cultivation)
The production of biological drugs recombinant
technology
Tissue cultures of higher organisms
primary cultures (subculturing or passaging not
possible)/ cell lines (tumor)
mostly adherent cell lines - release trypsin
Medium: ions , glucose, vitamins, nucleotides , lipids,
calf serum (source of growth factors, hormones + PDGF, EGF,
FGF, ... )
pH control, morphology
Vectors (details are kept secret): plasmids , viral plasmids
(retroviruses), polycations ( DEAE dextran)
Part of the transfected DNA are regions of DNA increasing
production (in units of g / L medium)
Selection (principles similar to those of S. cerevisiae . )
The production of biological drugs recombinant
technology
Tissue cultures of higher organisms
CHO – chinese hamster ovary
NS0, Sp2/0-Ag14 – mouse plasmocytome cells (leukocytes) –
auxotrophic for L-glutamine
BHK 21 (baby hamster kidney – syrian hamster)
The production of biological drugs recombinant
technology
Tissue cultures of higher organisms
production of „hybridomes“
The production of biological drugs recombinant
technology
Sobotková M, Bartůňková J. Remedia 2008, 18 (5), 356-364
Participant:0 Voted:0
Transgenic plants
„Edible vaccines " - production of the immunogenic protein (like the polio
vaccine )
culturing plant tissue culture in agar
Agrobacterium transfection (+ recombinant plasmid)
selection, planting
tobacco (Nicotiana tabacum ), Arabidopsis thaliana
PRX - 112 - 06/2014 - 1st patient treated with recombinant protein from the plant (
Protalix Biotherapeutics ) Gaucher disease - deficit of glucocerebrosidase
„…active recombinant proteins systemically through oral administration of plant cells
expressing biotherapeutic proteins...“
The production of biological drugs recombinant
technology
3 generation of biologicals
1 ) " copies " of human proteins
2 ) modified proteins (AAs substitution, glycosylation,
PEGylation) - better pharmacokinetics,
pharmacodynamics - e.g. glargine, PEG-IFN
3 ) de novo designed proteins / MAB
The production of biological drugs recombinant
technology
Contaminants from manufacture process
• Microorganisms - antigenic structures, pyrogenicity ,
sepsis
• Viruses
• DNA - ? Consequences?
• Custom product in improper 3D structure
• Contaminating proteins
– antigenicity
– stability (protease )
– safety (growth factors, hormones, toxins)
Purification - affinity gel / permeation chromatography
Contaminants from manufacture process
Purification - affinity gel / permeation chromatography
Purity ± 98-99 %
Verification of the biological activity of each
batch !
- Biochemical methods , cell lines or animal ( e.g. Epoetin )
= Time-consuming , cost , accuracy
The risk of functional damage of biologicals
• denaturation
• precipitation
• deamination
• mismatch of SH groups ( = incorrect 3D )
• oligomerization, aggregation, covalent binding
• hydrolysis
• isomerization
• racemisation
• formation imides
• oxidation
Multiple stabilizers
cryopreservation
metal chelation
checking the pH, osmolarity ,
strengthening the hydrophobic
bonds
Costs of drug development
Costs of the treatment
• Biological therapy is more expensive than "traditional" drugs
• Reasons - significantly higher development costs
- Demanding and complex testing
- The nature of products and higher costs after launch
- Higher costs for production, storage, transportation, shorter
expiration
consequences: lower numbers of treated patients (up to 2
orders !!! )
Despite that: effective and in many cases can save money in terms
of direct and indirect costs
direct costs: shorter hospitalization, reducing the number of
surgical procedures, reduce the cost of follow-up treatment , ...
indirect costs : accelerating the patient's self-sufficiency, reducing
the costs of absenteeism, cost reductions in social support and
care allowances , reducing the cost of informal care and nursing
103 CT on biologicals
(2017, biological | Open Studies | Phase 1, 2, 3, 0 |
NIH, U.S. Fed, Industry, Other)
103 CT on biologicals
(2017, biological | Open Studies | Phase 1, 2, 3, 0 | NIH, U.S. Fed, Industry, Other)
0 5 10 15 20 25
Infection
Immune System Diseases
Digestive System Diseases
Gastrointestinal Diseases
Neoplasms by Histologic Type
Virus Diseases
Intestinal Diseases
RNA Virus Infections
Skin Diseases
Gastroenteritis
Inflammatory Bowel Diseases
Respiratory Tract Diseases
Musculoskeletal Diseases
Arthritis
Joint Diseases
Central Nervous System Diseases
Collagen Diseases
Colonic Diseases
Connective Tissue Diseases
Neoplasms, Glandular and Epithelial
Rheumatic Diseases
Autoimmune Diseases
Bacterial Infections
Hypersensitivity
BIOSIMILARS
BIOSIMILARS
" Copy" of biotechnology drugs
• produced after the expiry of patent protection on the original
biotechnology drugs
• In the US, for the same group uses the term „Follow -on
Biologics“ , abbreviated „fobs“ .
The standard procedure for the registration of generic medicines
with defined structure ( ie . bioequivalence study) is
inapplicable
BIOSIMILARS
• Biosimilars drugs are similar, but not identical
with the original biological drug.
• Biosimilars are not automatically
therapeutically interchangeable with the
original biological drug .
• small change process in biosimilars may cause
an entirely different drug.
• Biosimilars pass before entering the market or
shorter simplified clinical trials , but
disproportionately more complex than with
generics
BIOSIMILARS
• after completeng „Centralised registration Procedure“
(mandatory for the registration of medicinal products
manufactured with sophisticated technology, particularly
biological drugs)
• compared the effectiveness and quality in studies similar to
those that are required for orig. preparation
• included in European Directives
• determining whether the product was evaluated in the same
dosage form, strength, by the same route of administration as
the ref. product and whether it was used in the same indication
e.g. growth hormone: 12 months
• comparative study of efficacy - safety within the RCT stage III
The price is about 10 times higher than for generic medicines
Biological drugs in a broader context
• Gene therapy
• Anti-sense therapy
• Immunization with vaccines
Biological drugs in a broader context
Gene therapy
• Incorporation of a gene sequence into a target tissue by an
appropriate vector approach
• treating or preventing gene-related illnesses by changing the
expression human genes
Gene therapy - vectors
• biological vectors of viral origin
– the most effective method of therapy
– retroviruses , lentiviruses , adenoviruses
• injection of naked DNA directly into the tumor
• genetic cannon - DNA wraps around gold particles
and scored into the epidermis - strong helium gun
• lipofections of DNA -coated liposome and delivered
into the tissue
• intravascular , intratracheal , oral…
Vectors for plasmids
Gene therapy SCID
• SCID severe combined immunodeficiency
• 1990 my first attempt at gene therapy on 4-year girl Ashanti DeSilva
• the T cells have been modified ex vivo
• normal ADA (adenosine deaminase) by a vector derived from MoMLV
(Moloney murine leukemia virus).
• The girl is still alive .
• 2002 -5 boys with severe X-linked SCID underwent gene therapy ex vivo,
with four times a year the state has improved significantly, with two of
them unfortunately died leukemia .
• Attempts suspended and perfecting the methodology
Gene therapy - the risks
• Adverse immune response
• Infections vector - natural activation of virus
• Genetic influence on gametes
• Risk of malignity- activation of protooncogenes ,
suppression of regulatory genes
Biological drugs in a broader context
Anti-sense therapy
– Incorporation of complementary oligonuleotides
to the initiation codon / promoter to DNA
– block the effects of action of proteins that are not
transcribed
• Olimersen - lowering expression of Bcl -2
(overexpressed in many cancer) - withdrawn form
registration
The antisense and gene therapy in
practice
• Fomivirsen - antisense sequences to the mRNA of human
CMV - Ophthalmic applications for pac . HIV + to reduce CMV
infection
• Pegaptanib - oligonucleotide binding to the VEGF protein for
the treatment of wet AMD
• Gencidin - adenovirus carrying the gene for p53 - From r .
2004 registered in China
• Glybera - 3 x 1012 genome copies of human lipoprotein
lipase in a viral vector (adeno- associated virus serotype 1
(AAV1 ) to treat hyperlipoproteinemia I
Clinical use of biological drugs
(selected examples)
Recombinant hormones
Insulin the first biological drug (1982)
- S. cerevisiae , E. coli - modified insulins (aspart, glulisine
detemir, glargin)
Glucagon - peptide, 29 AMK, E. coli i S. cerevisieae
GH - 191 AMK, 2x S-S bridge
- before biotechnological synthesis it was isolated from
hypophysis of dead people
- I: Turner sy. (caryotype 45, XO)
- 1977 (Nutropin, P. Seeburg, Genentech, UCSF)
IGF – growth failure
Recombinant hormones
Parathyroid hormone - 115 AA
Calcitonin - originally isolated from salmon
Gonadotropins - for IVF ( RG Edwards , Nobel. Prize , 2010)
FSH - follitropin α ( CHO cells) - hyperovulation
LH - maturation of oocytes, together with FSH
hCG - (CHO) cells - follicular maturation, support for ovulation
Biological treatment of autoimmune
diseases
1. rheumatic diseases
2. psoriasis
3. inflammatory bowel disease
4. asthma bronchiale
5. multiple sclerosis
6. ophtalmology
1. Biological Treatment of rheumatic diseases
Rheumatoid arthritis, juvenile idiopathic arthritis,
psoriatic arthritis , ankylosing spondylitis
Early intervention prevents irreversible changes;
Some of patients stay in sustained remission even after
treatment has stopped !
1. Biological Treatment of rheumatic diseases
Anti-TNF drugs
Infliximab – chimeric mAbs, IgG, 75 % of human,
25% of the murine antibody
high affinity binding to human TNFα
formation of stable complexes which bind complement
induction of apoptosis and lysis of the cells that produce TNFα , the
disintegration of granulomas
1. Biological Treatment of rheumatic diseases
Anti-TNF drugs
Adalimumab
- human MAB binds specifically to TNF and
neutralizes the biological function of TNF by blocking
its interaction with the p55 and p75 cell surface TNF
receptors
Golimumab
– human MAB wich bind to both soluble and
membrane bounbd TNFα
- the same mechanism action as infliximab
1. Biological Treatment of rheumatic diseases
Certolizumab – humanized Fab fragment of TNFα
antibody, konjugated with PEG
1. Biological Treatment of rheumatic diseases
Etanercept – binds TNFα
= soluble dimeric fusion protein – extracelulár domain
of receptor for TNFα and Fc chain of human IgG1
Mechanism of action: competitive inhibition of TNFα,
decreased effect of TNFβ
does not bind complement, but leads to the disintegration of
granulomas
1. Biological Treatment of rheumatic diseases
Anakinra – IL1 receptor antagonist („IL-1 RA“)
weaker effect than anti-TNF drugs
Rituximab - binds to the transmembrane antigen CD20
(on pre-B and mature B lymphocytes)
expressed on> 95% of all non-Hodgkin lymphomas of B
cell origin.
in combination with MTX , cyclophosphamide
Biological treatment of rheumatic diseases
anti-TNF drugs
opportunistic infections –
higher risk for: combination of immunosuppressive
drugs (with 2 - combined to 14x ! )
malnutrition
Age > 50 years
mycobacteria , listeria , fungal , viral infections
Adverse effects of anti -TNF agents
Adverse effects of anti -TNF agents
Paradoxical autoimmune reactions
anti-idiotypic antibodies (in addition prevents
binding of the antibody to TNF)
TB –activation of latent forms
Late carcinogenicity - lymphoproliferative disease
(2-3 times higher versus the healthy
population) , inconsistent data
Others - specific ADR for specific substances
1. Biological Treatment of rheumatic diseases
Abatacept - recombinant fusion protein from the extracellular
CTLA4 ( Cytotoxic T - lymphocyte - assoc . Antigen 4 ) ;
competitively binds to CD80 , thereby preventing T cell
proliferation –
in children not to be combined with anti-TNF therapy
(infectious complications)
Tocilizumab - humanized mAb against conventional IL6
AE: (infection ) + lipids increase ( CHOL , LDL, TAG)
2. The biological treatment of psoriasis
2. The biological treatment of psoriasis
Etanercept - see above
- Only one biological treatment of psoriasis for children 8-18 years
Infliximab - see above – s.c. admin 0th , 2nd, 6th week , then after 8
weeks
Ustekinumab - MAB fully human IgG1 anti-IL -12/ 23 (important in the
pathogenesis of psoriasis) inhibition of cytokine cascade sc at 0,
4 weeks, 12 weeks
AE : nasopharyngitis, headache, arthralgia, local irritation at the
injection site
3. Biological treatment of inflammatory bowel
disease
inflammatory bowel disease
Crohn's disease
ulcerative colitis
Anti-TNF drugs ( see above)
infliximab
adalimumab
certolizumab
3. Biological treatment of inflammatory
bowel disease
Natalizumab - IgG4 humanized MAB against
integrin α (on the surface of leukocytes, ensures
migration across the capillary wall )
Rescue treatment in Crohn D. (only in the US , in Czech
Republic registered for MS)
Vedolizumab - humanized mAb IgG1 against α4β1
integrin (on activated leukocytes , provides adhesion to
the endothelium and the penetration into the
circulation from the gastrointestinal tract )
3. Biological treatment of inflammatory bowel
disease
trichuris suis ova
3. Biological treatment of inflammatory bowel
disease
trichuris suis ova
15 clinical studies :
ulcerative colitis
Crohn's disease
psoriasis
celiac disease
diseases of the autism spectrum
4. Biological treatment of bronchial asthma
Adjunctive/supplementary treatment in patients with more serious
desease which do not respond to other treatments
–Omalizumab – humanized anti ab, bis IgE , s.c.
AE: malignancies?, parasitoses ... data not convincing
Mepolizumab - anti IL5 antibody
Infliximab/Golimumab/etanercept – anti TNFα
Off label, clinical benefit not convincing
4. Biological treatment of bronchial asthma
Other „problematic“ treatment
keliximab – MAB anti- CD4 , smaller study demonstrated effect on
pulmonary parameters ( PEF) ; studies have been stopped because
of concerns about the reduction in the number of CD4 cells
pitrakinra - inhibits the binding of IL- 4 and IL -13 to IL- 4Rα
subunit; may prevent worsening of FEV1 after allergen exposure ;
tested also in EA; requires further study
daclizumab - binds to CD25 inhibits the binding of IL- 2 receptor;
may decrease T-cell activation , improves FEV1 , in one study
alleviate symptoms ; 3 patients had serious adverse reactions
5. Biological treatment of multiple sclerosis
• demyelinating disease
• onset 20-40 yrs of age, women more frequently
• usually begins first clinical event (clinically isolated syndrome ,
CIS) includes visual, sensory or motor symptoms
Relaps-remitent form
Progresive form
• If untreated - after 10-20 years swithes in secondary progression - ↑
neurological disability in about 50 % after 15 years of physical disability and
cognitive dysfunction with serious socioeconomic consequences
Total direct + indirect costs of invalidized is 3 times higher than biol. treatment
5. Biological treatment of multiple sclerosis
Natalizumab - AB binds to α4β1 integrin of lymphocytes which
allow them to enter into the CNS (bind integrin subunit on
endothelial adhesion molecules before penetratvasion of
vascular wall)
It has a preventive effect on relapses and reduce the symptoms of
ongoing relapse
Adverse reactions: Serious opportunistic infections , rare ( 1 : 1000)
progressive multifocal leukoencephalopathy (PML) – risk
factors- JCV viral infection/antibodies, imunosupressant
treatment
iv at intervals of 4 weeks
5. Biological treatment of multiple
sclerosis
Glatiramer acetate – a mixture of synthetic polypeptides
derived from four AA ( Glu, Ala , Tyr , Lys )
- Peptide analog of myelin basic protein - suppresses
inflammation and also has neuroprotective properties
.
influences lymphocyte populations in the circulation by
induction of immunoregulatory Th2 lymphocytes
5. Biological treatment of multiple sclerosis
Anti-CD20 MAB (CD 20 lymphocytes )
rituximab
ocrelizumab
ofatumumab
alemtuzumab
Anti CD 25 MAB
daclizumab – humanized monoclonal antibody of IgG1 subtype that
binds to the Tac epitope on the interleukin-2 (IL-2) receptor αchain
(CD25), thus, effectively blocking the formation of the
high-affinity IL-2 receptor.
For severe attacks of MS
6. the treatment of viral hepatitis
IFNα, IFNβ –chronic infection HBV, HCV
Antivirotics - tenofovir, entecavir, adefovir, lamivudin
IFNα – „conventional“ is already not used
CIFN – consensual IFN - prim . structure according to the most
frequently occurring AAs in the sequence of all the known IFN
PEGylated – PolyEthylenGlycol – polymer of ethylene oxide prolongs
the half ( 7-10x ) , increases the plasma
concentrations do not change the absorption rate
- Protection against proteases
6. the treatment of viral hepatitis
PEG-IFNα2a – substituted monomethoxyPEG + IFN α2a
PEGylated – PolyEthylenGlycol – polymeric etylendioxid
– prolong halflife (upo to 100x)
PEG-IFNα2b – linear PEG + IFNα2b
Albumin-IFNα2b - recombinant protein, a fusion of two
genes ; efficiency , NA similar to the previous one,
1 application every 14 days ( longer half-life of albumin ) ,
higher price
6. the treatment of viral hepatitis
General ADRs IFN
• Frequent - flu-like syndrome . , chronic fatigue syndrome
- myelosuppression
- dysthymia , depression, anorexia
- weight loss, diarrhea
• Rare - inflammation at the injection site
- psychotic disorder , suicidal tendencies
- disorders of sex . functions
- acute heart failure
- Interstcial nephritis
The use of targeted/biological therapy in
ophthalmology
• used primarily substances with antiangiogenic activity (ie.
block of neovascularization)
• most importance for the process of angiogenesis , VEGF =
vascular endothelial growth factor
– important physiological functions
– located on the lining of blood and lymph vessels in the body
– regulates the proliferation and vascular permeability
– several types ( A - E )
• drugs used
– monoclonal antibodies (bevacizumab, ranibizumab)
– small drugs (pegaptanib, vortepofin)
– aflibercept= fusion protein
The use of targeted/biological
therapy in ophthalmology
• Bevacizumab - was developed for the treatment of
colorectal cancer, indication AMD is used off-label
MA : monoclonal antibody against VEGF (binds VEGF1 and
VEGF2 , blocks the interaction of DP. )
AE: acceleration of hypertension, proteinuria, thromboembolic
events, poor wound healing...
• ranibizumab
– Indications : AMD , CNV (chorioidal neovascularization)
– MA : fragment of a monoclonal antibody against VEGF - A
– short plasma half-life
– Administration 1x per month until the patient's visual
acuity is stable ( three consecutive monthly assessments )
Targeted therapy
• pegaptanib
– synthetic oligonucleotide
– the indication wet AMD
– MA : binds to receptor VEGF - A165
• vorteporfin
– as a single infusion is administered systemically
– always in combination with photodynamic therapy
• aflibercept
– MA : recombinant fusion protein; false receptor binds
VEGF-A and PlGF
Thank you for attention
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