Biomanufacturing:

Producing Novel Therapuetics

for Healthier Lives

Susan Sharfstein
Professor of Nanobioscience
ssharfstein@sunypoly.edu
 Albany, NY

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Colleges of Nanoscale Science & Engineering
NanoFab Complex

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 Traditional vs. New Pharmaceuticals

 Traditional Pharmaceuticals
 Small molecules that could be chemically
synthesized
 New Pharmaceuticals (biopharmaceuticals)
 Large macromolecules (proteins,
carbohydrates, nucleic acids) that are
synthesized by living organisms (bacteria,
yeast, insect and mammalian cells)
 Cell-based therapies including anticancer
drugs and regenerative medicine

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 Revolutionary New Drugs
 Tissue plasminogen activator (t-PA)
 An enzyme that breaks up blood clots, used to
treat heart attacks and strokes
 GCSF/GMCSF
 Used to restore white blood cells in
chemotherapy patients
 Tysabri ®
 Treatment for multiple sclerosis
 Blocks binding of α-4 integrins to VCAM-1;
prevents white blood cells from crossing the
blood-brain barrier

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 Cell-based Therapies

 CAR-T Cells used to treat blood cancers

(with more to come)
 Skin cells to treat burns and diabetic
ulcers
 Chondrocytes to repair cartilage defects
 Still to come-islet cells to treat diabetes,
bioarticifial livers
 Treatments for cardiovascular and
neurodegenerative diseases

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 Safer Old Drugs

 Insulin
 Human vs. Porcine or Bovine
 Human growth hormone (hGH)
 Treats some forms of dwarfism in children
 Blood clotting factors
 No longer purified from human blood
 Heparin-still a slaughterhouse product

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 Biologics and Biomanufacturing

Image courtesy Genentech GENE TECHNO SCIENCE

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 Small Molecule and Biologic Drug
Approvals

Nature Reviews Drug Discovery 17, 81–85

(2018)
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“Duck for President” -- Doreen Cronin, 2004

2/11/22
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DNA-Deoxyribonucleic Acid contains all the
genetic information for ALL living things
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 Nucleotides are used
to form nucleic acids

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 Names and Abbreviations of
Nucleic Acid Bases,
Nucleosides, and Nucleotides

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Basics of Gene Expression (Central Dogma)

Deoxyribonucleic acid (DNA)-genetic

material, composed of 4 bases, ATGC
(adenine, cytosine, guanine, thymine)

transcribed
Ribonucleic acids (RNA),
composed of 4 bases, AUGC (uracil
replaces thymine)
translated

Proteins, composed of 20 amino

acids
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 Double-stranded DNA.
Page 18

Voet Biochemistry 3e
© 2004 John Wiley &
Sons, Inc.

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 Protein functions

 Structural proteins: glycoproteins,

collagen, keratin
 Catalytic proteins: enzymes
 Transport proteins: hemoglobin
(oxygen), serum albumin (lipids)
 Regulatory proteins: hormones
(insulin, growth hormone), cytokines,
growth factors
 Protective proteins: antibodies,
thrombin

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 Conversion of DNA information into proteins

 We know that DNA is the genetic material

and it is broken into genes which “code”
for proteins.
 Proteins are made up of 20 different
amino acids. DNA is made up of 4
different nucleotides.
 How many nucleotides are necessary to
create a 20-word alphabet?
Answer – 3
1 nucleotide – 4 words
2 nucleotides – 16 words
3 nucleotides – 64 words

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Each 3-letter sequence is called a
codon
The genetic code is relatively
conserved across all species
Why is the genetic code degenerate?
•Reduce the effect of mutations
•Vary the G/C content. DNA high in
G/C content has a higher melting
temperature
AUG codes for the start of the
translation sequence

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 How do we get from DNA to proteins?
 DNA is transcribed into RNA sequences
 RNA is translated into protein sequences
Proteins can only be the
recipients of genetic
information

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 PTI History of Biopharmaceuticals
2002
Adalimumab, a fully human
antibody generated using phage
display technology, approved to
treat autoimmune diseases
(Abbot)
1997
First whole chimeric antibody,
rituximab to treat autoimmune
diseases and cancer (IDEC) and
1987 first humanized antibody,
Recombinant human tissue daclizumab to treat MS (PDL
1961 Biopharma), approved.
plasminogen activator produced
Genetic code deciphered, 1975
in Chinese hamster ovary cells
permitting genetic Kohler and Milstein
introduced (Genentech)
engineering introduce hybridoma
technology

1982 1994
1953 Recombinant human Abciximab, a chimeric antibody 2015
First accurate model of insulin made in E. fragment is approved to prevent First biosimilar Filgrastim-sndz
DNA suggested (Watson Coli approved platelet aggregation during (granulocyte colony-stimulating
and Crick) (Genentech) stent placement (Centecor) factor) to stimulate neutrophil
recovery during chemotherapy
1986 (Sandoz) approved in US
Muromonab-CD3 a murine
monoclonal antibody to prevent
transplanted organ rejection
approved (Ortho
Pharmaceuticals)

http://www.biopharminternational.com/protein-therapeutics-and-
regulation-quality-brief-history?pageID=1

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Science of Recombinant
Protein Production

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Expression Systems

 Bacteria
 Yeast
 Mammalian
 Insect
 Transgenic Plants
 Transgenic Animals

17Oct08 22
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 Antibody (immunoglobulin)
Structure

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 Monoclonal Antibody Production

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Scientific American, October 2001
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 Why Have Monoclonal Antibody Therapeutics
Taken So Long to Come to Fruition?

 Original mAbs were murine – repeated

injections resulted in severe immunological
reactions, causing joint swelling, rash, kidney
failure, and death
 To alleviate these problems, Abs must be
modified to appear more human
Scientific American,
v285 p 38 2001

2/11/22
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How cells are grown

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 What does biomanufacturing look like?

https://moneyinc.com/biomanufacturing/

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Non-protein therapeutic
biologics

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GENE THERAPY

Dr. S. Moses Arunsingh

BIRO
25.03.2011
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 Human Genome Project

 The human genome contains

3164.7 million chemical
nucleotide bases (A, C, T, and
G).
 The total number of genes is
estimated at 30,000.
 Less than 2% of the genome
codes for proteins.
 The functions are unknown
for over 50% of discovered
genes.
  Almost all (99.9%)
nucleotide bases are exactly
the same in all people.
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 Gene Therapy

 Gene therapy is an experimental technique

that uses genes to treat or prevent disease.
 Replacing a mutated gene that causes disease
with a healthy copy of the gene.
 Inactivating, or “knocking out,” a mutated
gene that is functioning improperly.
 Introducing a new gene into the body to help
fight a disease.

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 CAR T-cells: a
cancer
immunotherapy

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 Chimeric antigen receptors (CARs)
CAR T-cell therapy or adoptive cell transfer

 Can we use the body’s native immune

system (or a modification of it) to treat
cancer?
 Current treatments
 Surgery
 Radiation
 Chemotherapy
 Antibody-based therapies

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 Goal: To generate T-cells that recognize antigens
on tumor cells

Illustration of the components of second- and third-generation chimeric antigen receptor T

cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted
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Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)
 Regenerative Medicine

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Regenerative medicine for arthritis

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 Challenges for regenerative medicine

 Biology-how to get the cells you want

 Engineering- how to get 10 billion of the
cells you want
 Medicine- how to introduce them into
the place you want and have them
integrate in with existing tissue

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