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Drug discovery & development with a focus on personalization and biologics

Protein drugs group work kick-off

TMED-929A

November 4, 2020

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Michael Jeltsch (michael.jeltsch@helsinki.fi)

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These slides: mjlab.fi/ddko

Source files: mjlab.fi/dd-files

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Creative Commons what?

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This presentation: mjlab.fi/dd

Editable source files: mjlab.fi/dd-files

This work is licensed under the Creative Commons Attribution-Share Alike 4.0 International license. You are free:

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Tasks for this session

Tasks for this session

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Introduction of teacher & participants

Short introduction of 9 possible drug choices

Instructions and agreement on “interim report” meetings

Group formation (4 groups of 4 students or 4 groups of 3 students + one 4-student-group), drug selection, group naming

What do you want to learn this course?

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Drug Development

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Different types of biologics

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Vaccines

Gene therapy

Cell

therapy

Proteins

Transplants

  • Antibodies:�polyclonal (“antisera”) & monoclonal
  • Protein hormones, growth factors�& cytokines
  • Protein toxins

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Focus on biologicals (protein drugs)

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(Protein) biologics

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Interesting biological drugs

  • Aranesp (Darbepoetin alfa, erythropoietin homolog)
  • Avastin (Bevacizumab, anti-VEGF-A antibody)
  • Botox (OnabotulinumtoxinA)
  • Eylea (Aflibercept, soluble VEGF-A receptor)
  • Herceptin (Trastuzumab, anti-HER2-antibody)
  • Humira (Adalimumab, first fully human Ab, anti-TNF⍺ antibody)
  • Insulin (incl. derivatives like glargine, long-acting insulin)
  • Lymfactin (AdVEGF-C, not on the market yet)
  • Pegfilgrastim (GCSF)
  • A drug of your own choice?

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Biological drug #1: Aranesp®

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Aranesp® (Darbepoetin alfa)

  • Homolog of the endogenous protein hormone erythropoietin (“Epo”)
  • Five point mutations to create NXS/T sites to increase the biological half life
  • Stimulates red blood cell production

https://doi.org/10.1002/dta.1341

image credits: TRANSMED

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Biological drug #1: Aranesp®

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  • Indications: several types of anemias
  • Available in Finland: yes
  • Company: Amgen (US)
  • Interesting: The name erythropoietin was coined in Finland by Eeva Jalavisto & Eva Bonsdorf
  • Market introduction: 2001

image credits: CiclismoItalia

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Biological drug #2: Avastin®

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Avastin® (Bevacizumab)

  • Humanized mouse monoclonal antibody
  • Suppresses the growth of blood vessels (“anti-angiogenic”)
  • Hypothesis: Tumors need blood vessels to grow big

https://doi.org/10.1016/j.bbrc.2005.05.132

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Folkman, Dvorak, Ferrara

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1997

1971

Judah Folkman proposes the concept

of antiangiogenic tumor therapy

1992

1983

Napoleone Ferrara generates neutralizing

mouse antibodies against VEGF

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Harold Dvorak isolates Vascular Endothelial Growth Factor (VEGF)

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Clinical trials start with the humanized

anti-VEGF antibody (“bevacizumab”)

2004

Bevacizumab receives FDA approval

for treatment of colon cancer

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Biological drug #2: Avastin®

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  • Indications: different cancers (colorectal, lung)
  • Available in Finland: yes
  • Company: Genentech (US) →
  • Interesting: This drug was predicted in 1971 by Judah Folkman
  • Market introduction: 2004

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Biological drug #3: Botox®

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Botox® (OnabotulinumtoxinA)

Botulinum toxins (BTs)

  • A group of neurotoxic proteins produced by some species in the bacterial genus Clostridium.
  • Size: ~150 kDa
  • Botulinum toxin type A is the most lethal, naturally occurring toxin known to man.

https://doi.org/10.1016%2Fj.coph.2004.12.006

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Biological drug #3: Botox®

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  • Indications: different spasms, chronic migraine, strabismus (“crossed eyes”)
  • Available in Finland: yes
  • Company: Allergan, Inc (US) →
  • Interesting: Used as a bioweapon
  • Market introduction: late 1970s

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Biological drug #4: Eylea®

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Eylea® (Aflibercept)

  • Soluble VEGF-A receptor, works like Avastin (antibody)
  • Suppresses the growth of blood vessels (“anti-angiogenic”)
  • 3-part fusion protein from VEGFR-1(D2), VEGFR-2(D3), and IgG1Fc

https://doi.org/10.1007/s40123-013-0015-2

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Biological drug #4: Eylea®

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  • Indications: wet macular degeneration, diabetic retinopathy (~ growth of blood vessels from the choroid into the retina)
  • Available in Finland: yes
  • Company: Regeneron (US)
  • Interesting: “me-too-drug”
  • Market introduction: 2011

image credits: ttfnrob

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Biological drug #5: Herceptin®

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Herceptin® (Trastuzumab)

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Antibody against ERBB2 (HER2)

  • ErBB2 = tyrosine kinase receptor
  • Overexpressed in ~15-30% of breast cancers
  • One of the oldest mAbs still in use

https://www.gene.com/stories/her2/

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Biological drug #5: Herceptin®

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  • Indications: ERBB2+ breast cancer
  • Available in Finland: yes
  • Company: Genentech (US) →
  • Interesting: ERBB2 is a receptor, but it has no known ligands, several biosimilars available since 2017
  • Market introduction: 1998

10.3390/cancers11121826

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Biological drug #6: Humira®

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Humira® (Adalimumab)

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Antibody against TNF-⍺

  • Anti-inflammatory treatment for Inflammatory autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, etc.)
  • Lots of patent issues!
  • Many biosimilars!

https://commons.wikimedia.org/wiki/File:Components_�of_an_Adalimumab-Humira_pen_-_annotated.jpg

10.2147/BS.S98177

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Biological drug #6: Humira®

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  • First phage-display-derived monoclonal for human therapy
  • Available in Finland: yes
  • Company: BASF/CAT → AbbVie
  • Interesting: best-selling drug considering revenues, in Covid-19 treatment trials
  • Market introduction: 2002

10.3390%2Ftoxins10060236

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Biological drug #7: Insulin

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Insulin

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  • First human successful treatment in 1922 with bovine (= cow) insulin (team Banting, Best & Collip)*
  • Size: ~5.8 kDa
  • Since 1982: human insulin (recombinant human insulin produced in E. coli bacteria)

https://doi.org/10.3389/fendo.2018.00613

*The fact that pancreatic insulin-containing extracts were able to treat diabetes had been discovered three times independently before (by George Ludwig Zuelzer in 1906, Israel Kleiner in 1915, Nicolae Paulescu in 1916).

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Biological drug #7: Insulin

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  • One of the oldest protein drugs
  • Available in Finland: yes
  • Companies: many different
  • Interesting: worldwide >400 million patients (2019, 90% Type 2)
  • Market introduction: 1922 (FDA?)

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Biological drug #8: Lymfactin®

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Lymfactin®

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The first drug for treating secondary lymphedema

  • Lymphedema: swelling of body parts due to insufficient lymphatic transport
  • No approved drug or causal treatment
  • Recombinant adenovirus producing a growth factor for lymphatic vessels

https://herantis.com/pipeline/#lymfactinsupsup

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Biological drug #8: Lymfactin®

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  • Indications: secondary (acquired) lymphedema
  • Available in Finland: yes
  • Company: Herantis Pharma
  • Interesting: developed in FIN
  • Market introduction: ? (in phase II clinical studies)

10.1016/j.bjps.2020.05.009

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Biological drug #9: Pegfilgrastim

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Pegfilgrastim (GCSF)

  • Stimulates neutrophil production (most common white blood cell, normal: 100 bn cells/24h)
  • Indication: Prevention of infections during chemotherapy or acute radiation syndrome, bone marrow donation/stem cell transplantation
  • Many biosimilars

10.1007/s40259-015-0127-4

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Biological drug #9: Pegfilgrastim

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  • Available in Finland: yes
  • Company: Amgen
  • Market introduction: 2002
  • Interesting factoid: G-CSF does not contain a single Asn amino acid residue

10.2165/00003495-200262080-00012

Image credits: Franziska Geiser

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Group work in breakout sessions

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  • Group formation (4 groups of 5 students or 5 groups of 4 students)
  • Drug selection
  • Group naming based on the drug
  • Prepare to give your reasons for choosing the specific drug
  • It would be preferable if all groups choose different drugs.

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Practicalities for the group work

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  • Presentations should be 10-15 minutes.
  • If you really want to do another drug (not one of the 9 choices), please let me know!
  • Each group organizes their meetings & works on its own.
  • Before the presentation day (27.11.), each group submits Version 1 of the presentation to allow for possible additions/improvements and meets with the teacher once to discuss possible additions/improvements. A Doodle will be made available after this session for the groups to select a suitable meeting time.
  • Each group chooses an opponent group for the presentation. The opponent group is supposed to ask relevant questions, point out omissions, etc. Each group can only act as opponent group once.

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That’s all, folks!

That’s all, folks!

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This presentation: mjlab.fi/ddko

Feedback: michael.jeltsch@helsinki.fi, michael@jeltsch.org

Lab: mjlab.fi (www.helsinki.fi/fi/tutkimusryhmat/lymphangiogeneesitutkimusta-ja-vasta-aineteknologia)

Private rumblings: jeltsch.org(/science)

Core facility: b3p.it.helsinki.fi

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Jeltsch Lab & UH