Ex 3 L2: Biologics pt 1

Question 1

Biologics

Answer 1

(biopharmaceuticals, large molecules) are medicinal agents derived from living systems in contrast to more conventional “small molecule” drugs produced by chemical synthesis

Question 2

Biologics examples

Answer 2

Recombinant proteins, blood factors, mRNA, vaccines and cell and gene therapies

Peptides and oligonucleotides (“tides”) have properties intermediate between small and large molecules are also included here
-act like proteins but are not made in the body

Question 3

Types of biologics (full) and common features

Answer 3

Recombinant proteins
Plasma immunoglobulins (IVIG)
Some peptides
Vaccines
DNA
RNA, mRNA
Cell and gene therapies
Cell-based therapies
AAV vectors
Gene editing (CRISPR)

Common features
Biological origin
-Animal
Cellular /molecular biology
High MW
High Order structure
-Use cells as a factory for making other cells
-Though to use mRNA or cell itself as a drug

Question 4

Early biologics: Insulin in the 1920s

Answer 4

Extraction of porcine insulin from pig pancreas at Eli Lily:
-High sequence of homology among human, porcine, bovine insulin

-Structure of insulin is highly conserved from species to species (AA sequence is the same)

Question 5

Early biologics: Making flu vaccine in eggs, 1957

Answer 5

Eli Lilly and Co. workers in Greenfield IN
-Candidate vaccine viruses (CVVs) are grown in chickens
CVVs are then injected into fertilized chicken eggs are incubated for several days
The fluid containing virus is harvested from the eggs
Vaccine viruses are inactivated(killed) and the virus antigen is purified
This process is still used today

Question 6

Recombinant proteins: From the 1980s

Answer 6

Central dogma of biology
-First recombinant human insulin, Eli Lilly October 1982
-Bacterial Cell as a protein factory
-Development of methods to grow cells in culture, isolate and purify the protein produced

Recombinant: Take bacteria w/plasma in it, cut the plasma via enzyme, and insert engineered plasma into bacteria.
Same thing can be done in mammalian cells
Glycosylation

Question 7

Recombinant proteins: mAbs

Answer 7

Today, the leading recombinant protein drugs are monoclonal antibodies (mAbs)

First mAb - OKT3 was approved in 1986

mAbs are high molecular weight (~150,000 DA (insulin 5808 Da)

mAbs contain two light chains (L) and two heavy chains (H) linked by disulfide bonds

mAbs are produced in mammalian cells (eg. Chinese Hamster ovary, CHO), because posttransitional glycosylation (glycans) is important to their structure and function

Question 8

Cell therapies: CAR-T

Answer 8

In August 2017, FDA approved first chimeric antigen receptor T cell therapy

Kymirah is the first living drug an autologous T cell therapy
-t cells are removed from a patient’s blood
-Transfected with an antigen receptor that recognizes a cancer antigen
-grown in culture
-returned to the patient and infused
-Contrast: allogeneic therapy
Allogenic - ideally will be able to give everyone the same type of cells one day

Question 9

mRNA vaccines: The new revolution, ca 2020

Answer 9

The mRNA vaccines for COVID-19 contain mRNA in lipid nanoparticles (LNP)
The mRNA codes for the spike protein of the virus
the LNP contain four types of lipids that condense mRNA and enable delivery to the cytoplasm
The rapid intro of these vaccines has started the “mRNA revolution”

Question 10

Biologics: The cast of characters

Answer 10

DNA
mRNA
Cells
Proteins
Viral vector
Animal Source

Question 11

Biologics: The changing plot

Answer 11

Early biologics - isolated from animals
-Isolated from animal tissues

Recombinant proteins - expressed in transferred cell lines
-Recombinant proteins are produced by transfected cells that acts as protein factories

Question 12

Biologics today: The characters play many roles

Answer 12

protein factory
-Therapeutic agent (e.g. CAR-T)
-Therapeutic target

Transfection reagent
-Therapeutic agent
-Therapeutic target (e.g. COVID-19)

Therapeutic agent (mABs)
Therapeutic target (receptor)

Instructions for transfected cells
Therapeutic

Question 13

Growth of biologics: Top 10 prescription drugs 2001-2022

Answer 13

Biologics
-Procrit
-Enbrel
-Remicade
-Humira
-Rituxumab
-Lantus
-Avastin
-Herceptin
-Keytruda
-Eylea
-Stealara

Biologic mRNA
-Comirnaty
-Spikevax

Question 14

In 2017 _/15 top drugs were biologics

Answer 14

11
-Lantus
-Prevnar13
-Neulasta
-Humira
-Enbrel
-Eyela
-MabThera
-Remicade
-Herceptin
-Avastin
-Opdivo

Question 15

Dosage forms for Biologics

Answer 15

Dosing is usually parenteral
-Because biologics are degraded extensively in the GI tract
-Exceptions: oral vaccines, some orally administered peptides

Common dosage forms for biologics include
-Solution for injection
-Pen or autoinjector
-Pre-filled syringe
-Lyophilized powder for reconstitution

Question 16

Biologics Part 1: Summary

Answer 16

Biologics are an important and rapidly growing class of drugs
-Major types of biologics are mAbs, mRNA, cell and gene therapies, and vaccines. Nucleotides and peptides will also be discussed
-Most biologics are admin parenterally
-Major dosage forms for biologics are solutions for injection, pens and autoinjectors, pre-filled syringes and lyophilized solids for reconstitution