Biologics or biological drugs

officially (WHO) „biological and biotechnological substances“
Basic characterisation of biologics

typically obtained by other way than by classical chemical synthesis
(semisynthetic modifications are possible)
typically Mr
> 1000 (up to 1000 „small molecules“) - greater, more complex,
usually exhibit a primary structure (a sequence of amino acids or nucleotides), a
secondary structure (-helix, “folded sheet”, influence of -S-S- bridges), a
tertiary structure (general space arrangement of a monomeric molecule) and a
quraternary structure (grouping of monomers); many proteins are glycosylated

given parenterally as they due to their hydrophilicity and big Mr cannot be
absorbed from GIT

but all above conditions need not be necessarily fulfilled for classification of a drug as a
biologic © Oldřich Farsa 2020
Some possible problems in terminology

pharmaceutics = technology of manufacturing of application forms of drugs
(“pharmaceutical technology” is the literal translation from Czech)


biopharmaceutics  biopharmacy = „a discipline concerning drug absorption” on a
frontier of pharmaceutics and pharmacokinetics (pharmacology)

biologicals: analogy to chemicals  they include „biological drugs“ but also diagnostic
monoclonal antibodies, enzymes used in technology etc.

biologics: the term mostly used for „biological drugs“

„Biopharmaceutics“ is not a suitable name for a subject devoted to “biological drugs”, but
is also used.
Differences in production of “small molecules” and biologics

small molecules – classical organic synthesis: chemicals with exactly defined chemical
structure and purity react under exactly defined conditions with a predictable and preciously
verifiable results

biologics- preparation by „harvesting“ of compounds produced ancreted by artificially
constructed cells (genetic engineering)
An illustration of the difference between a biologic and a “small molecule”
erythropoietin and acetylsalicylic acid
History of biologic therapeutics

the Antiquity and the Middle Ages: usage of leeches for treatment of circulation and blood
disorders (hirudin)

classical vaccines: preparation of dead or attenuated bacterial cultures or attenuated or
inactivated viruses (e.g. pox: transfer of the infection „from a skin to a skin“ has been known
long since around 1000 A.D. in China; 1796 – Edward Jenner demonstrated that putting of
the purulence from a furuncle of the cowpox in under the skin protected against the infection
with pox; 1805 – 1st
vaccine against pox was prepared on the calf skin in Italy; 1864 – mass
usage of this vaccine; after 1940 – lyofilized vaccines (Collier))
Edward Jenner. Lithograph based
on the painting by J.R. Smith
(1801).
Courtesy of the Institute of the
History of Medicine, The John
Hopkins University,
where the original painting is on
display.
The cowpox lesion on the hand of the
milkmaid, Sarah Nelmes,
from which Jenner took pustular material to
inoculate the boy James Phipps,
May 1796. Case XVI of Edward Jenner’s
1798 report on vaccination (2).
History of biologics - continued

(poly-clonal) antibodies („sera“) - immunisation of a suitable production macro-organism (eg.
horse, rabbit) with a noxious agent (a toxin, e.g. a snake poison), a serum acquired from the
blood used as an antidote; monoclonal antibodies for analytic and diagnostic purposes, then a
suitable transformation (RIA, ELISA)

peptides – isolation from biological material (insulin: Banting and Best 1921)
Production of polyclonal antibodies from horse antisera.
More recent history of biologic therapeutics – genetic engineering

1977 - somatostatin first time prepared by a recombinant technology in E. coli
(Genetech, USA)

1978 – human insulin cloned

1982 – recombinant human insulin prepared in E. coli marketed

1984 – Factor VIII of the blood clotting first time prepared in a laboratory

1985 – FDA approved somatrem, a somatotropin analogue

since 1980th
– development of therapeutic monoclonal antibodies (mabs)

in 1980th 80 % of mabs of mouse origin, in 2000th only 7 %

OKT3 - murine anti-CD3 antibody was the first mab approved by FDA for
treatment of organ transplant rejection
History of biologics from the point of view of a corporation
(Genetech)
Development and authorisation of biologics
EMA (EU): normal approval procedure like for any other drug
FDA (USA): possibility of taking part into so called Fast Track Drug Development Program
(since 1998, revised 2004) – the prerequisite is the usefulness for serious or life
endangering condition and legitimated hope for better clinical efficacy than up to the
present time used drugs
Generics and „biosimilars“
Generics: small molecules – contain the same active compound as the original and
reach 80 – 105 % of the bioavailability of the original
„Biosimilars“ (EMA) = „follow-on proteins“ = „similar biotherapeutic products (WHO) =
„similar biologics“ (India) aj. - contain the drug prepared by the similar way and with the
chemico-physical and analytical characteristics closely similar to the original (=
„originator product“) but the same activity must be clinically demonstrated at least in its
main indication
Different approaches of FDA (USA) and EMA (EU)

EMA: consistent testing of effects in the relationship to the proposed therapeutic usage;
the security of the patient is fundamental; neither generic prescription nor substitution
among biosimilars

FDA: more liberal approach; full support for „biosimilars“ approvals
Committee for Medicinal Products for HumanCommittee for Medicinal Products for Human
Use (CHMP) Guideline on Similar BiologicalUse (CHMP) Guideline on Similar Biological
Medicinal ProductsMedicinal Products
(CHMP/437/04)
“It should be recognised that, by definition, similarby definition, similar
biological medicinal products are not genericbiological medicinal products are not generic medicinal
products, since it could be expected that there may be
subtle differencessubtle differences between similar biological medicinal
products from different manufacturers or compared with
reference products, which may not be fully apparent untilmay not be fully apparent until
greater experience in their use has been establishedgreater experience in their use has been established.
Therefore, in order to support pharmacovigilance
monitoring, the specific medicinal product given to the
patient should be clearly identified.”
Pharmacological classification of biological and biotechnological substances in
accordance with WHO

Drugs for alimentary tract and metabolism: insulins.

Anti-infectives: antimicrobial, bactericidal permeability increasing polypeptides, human
papilomavirus.

Antineoplastics: peptide vaccines, recombinant vaccines, toxins.

Blood and agents acting on the heamopoietic system: antithrombins, blood coagulation cascade
inhibitors, blood coagulation factors, erythropoietin type blood factors, heparin derivatives
including low molecular mass heparins (heparinoids), hirudin derivatives, trombomodulins.

Immunomodulators and immunostimulants: colony stimulating factors, inteferons, interleukin
receptor antagonists, interleukin type substances, monoclonal antibodies , receptor molecules,
native or modified, tumor necrosis factor antagonists.

Hormones, hormone antagonists, hormone-release stimulating peptides or hormone-release
inhibiting peptides (excluding insulins): growth hormon (GH) derivatives, its antagonists, oxytocin
derivatives, pituitary / placental glycoprotein hormones, pituitary hormone-release stimulating
peptides, synthetic polypeptides with cortikotropin-like action, vasoconstriktors, vasopressin
derivatives.

Various: „antisense“ oligonucleotides, enzymes, gene therapy products, growth factors, peptides
a glycopeptides not classified above.
Basics of biologics nomenclature in accordance with WHO recommendations
[INTERNATIONAL NONPROPRIETARY NAMES (INN) FOR BIOLOGICAL AND BIOTECHNOLOGICAL SUBSTANCES (A
REVIEW) INN Working Document 05.179 Update December 2010]
Basics of biologics nomenclature in accordance with WHO recommendations
(continued)
Basics of biologics nomenclature in accordance with WHO
recommendations
(continued)
Chimeric vs. humanized monoclonal antibodies
Nomenclature of monoclonal antibodies – continued
a sub-stem A for disease or target class is situated before a sub-stem for source of the product:
Nomenclature of monoclonal antibodies – continued
Special sub-stems for tumours were in the older version of INN rules from 2007 and
are not recommended in the newer one
An example of the INN name of a monoclonal antibody
humanized

prefixbevacizumab

cardiovascular
Nomenclature of monoclonal antibodies – continued
Disadvantages of biologics (except adverse effects, which are in
general the same as in small molecules)

imunogenicity – induction of formation of antibodies against the drug

HAMA – human anti-mouse antibodies – formed against mouse peptide sequences in
chimeric biologics (similarly HARA – human anti-rat antibodies)

greater than 20% of murine antibodies induce only tolerable/negligible immunogenicity

HAHA – human anti-human antibodies – formed against fully human antibodies or other
biologics; bound to a unique binding site, where they are not tolerated by the immunity system

humanization of some murine antibodies may reduce their clinical effectiveness

neutralizing  non-neutralizing; if they are neutralizing, they attenuate the efficacy of
treatment

formation of antibodies against drugs (e.g. compounds acting against TNF) depends also on
presence of infection

high price (partly except biosimilars)

activity and security frequently insufficiently guaranteed

poor biological availability requiring special methods of application