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PCL102 > L12: Biologics and Specialty Drugs > Flashcards

L12: Biologics and Specialty Drugs Flashcards

1
Q

what are biologics

A

They are medicinal products used to either:
* Treat or cure diseases and medical conditions
* Prevent diseases
* Diagnose diseases

Produced from living cells or organisms
* Derived from a variety of natural sources

May be composed of:
* Protein, nucleic acids or sugars, or combinations of these substances
* Living entities such as cells and tissues

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2
Q

Where are biologics created from

A
  • created by living things
  • mamalian cell culture, humans, bacteria, mice, yeast etc.
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3
Q

what are the types of biologics

A
  • blood derivatives
  • whole blood
  • vaccine
  • proteins
  • human tissues
  • allergenic extracts

etc.

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4
Q

small molecule drugs vs biologics

source
size
chemical properties
manufacturing process
form
dispensed by

A

Small Molecule drugs (SMD)
source: chemical synthesis
size: generally low molecular weight (<1000 Da)
chemical properties: known structures that are well characterized
manufacturing process: fewer critical process steps (ex. 10 steps)
form: generally oral solids*
dispensed by: usually retail pharmacies*

biologics
source: made from/with living cells/organisms
size: generally high molecular weight (»1000 Da)
chemical properties: complex mixtures that are less easily characterized
manufacturing process: many critixal process steps (ex. 100 steps)
form: often injected or infused *
dispensed by: often by doctors or hospitals*

*= generalization

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5
Q

what is the size and complexity analogy between small and large biologics and SMDs

A

SMD
size = asprin -21 atoms
complexity = bikes -20 lbs

small biologic
size = human growth hormone -3000 atoms
complexity = car -3000 lbs

large biologic
size = antibody -25000 atoms
complexity = business jets -30000 lbs

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6
Q

describe peptides as biologics

(insulin)

A

Peptides
* Chains of amino acids
* Insulin (1982), first medical peptide to be produced by recombinant DNA technology
–> World Health Organization List of Essential Medicines
- Insulin is a peptide hormone containing two chains cross-linked by disulfide bridges
* GLP-1 agonist peptides

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7
Q

what is the manufacturing process like for insulin

using genetic engineering and DNA– how do they make insulin from recombinant dna commercially?

A

they take a plasmid (loop of bacterial dna) from a human insulin gene and transform it to a recombinant bacterium

  • to do this they ferment the bacterium with the plasmid to make recombinant bacterium with insulin, then they harvest the insulin
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8
Q

what are biologics produced in

A

Produced by bio-reactors (must keep these machines running safe and are clean)

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9
Q

How are biologics used in cell therapies (2)

what does allogeneic and autologous mean?

A

Allogeneic = use a universal donor’s cells

Autologous = collect cells from the patient

after cells are collectures, they are processed, expanded in the lab, and reinjected in the patient

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10
Q

examples of biologics from first in human (2)

how does Bo’s therapy work to treat cancer?

A

Anita: Tumour Infiltrating Lymphocytes (TIL)

Bo = Chimeric Antigen T (CAR-T) Cells

CAR-T therapy
- collect blood to obtain T cells
- T cells are separated and removed
- T cells are genetically altered to have special receptors called CAR receptors
- millions of CAR T-cells are grown
- chemotherapy is given before CAR-T cell therapy
- new CAR-T cells are introduced into the bloodstream

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11
Q

how is stem cell therapy used for parkinson disease - phase 1 clinical trial, toronto

A
  • The human embryonic stem cells are designed to replace the dopamine producing neurons that are lost in parkinson’s disease
  • In a surgery, these neuron precursors are implanted into the brain of a person with Parkinson’s disease.
  • When transplanted, they have the potential to reform neural networks that have been severely affected by Parkinson’s and restore motor and non- motor function to patients.
  • Encouraging phase 1 trial results, October 2023. 12 patients. Safety and tolerability assessed at 1 year post-injection.
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12
Q

Antibodies are a type of biologic. what is an antibody and how do they react with antigens to eliminate pathogens?

A
  • Antibodies are proteins which play a pivotal role in our immunity against pathogens (e.g. bacteria, viruses)
  • Our bodies generate antibodies to bind to the antigens on the surface of the virus or bacteria
  • Once bound, the antibodies neutralize the pathogen directly or attract other parts of the immune system to eliminate the pathogen
  • Antibodies may also be used to treat diseases such as cancer or inflammation
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13
Q

what is the structure of antibodies? variable and constant structures

A
  • Antibodies are Y shaped proteins

Each antibody consists of:

–> Variable region at the tip of the antigen:
* Recognizes and binds the antigen
* Each antibody-producing cell in the body makes antibodies with a specific variable region (like an active site)
–> Constant region:
* Determines the mechanism used to destroy the antigen
* Antibodies are divided into five major classes based on their constant region structure and immune function

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14
Q

what are monoclonal vs polyclonal antibodies?

A

Polyclonal antibodies:
- Complex mixture of antibodies produced by many different antibody-producing cells
* Each individual antibody in the mixture recognizes and binds to different areas on the antigen

Monoclonal antibodies (mAbs):
- Identical antibodies derived from a single antibody-producing cell (or clones of that cell)
* Each mAb will only recognize and bind to a single specific site on the antigen
* Preparations of mAbs are produced in a laboratory

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15
Q

explain the process of mAb discovery: mAb production

A
  1. Target antigen injected into a mouse to start the production of antibodies (Abs)
  2. Collection of Ab-producting cells from the mouse are fused with immortal cancer cells to create hybridoma capable of unlimited growth
  3. Hybridomas screened for desired Ab production
  4. desired ab-producting hyboridoma grown in culture
  5. purification of MAb
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16
Q

Describe antibody engineering using mouse mAbs

  • how does the human immune system react to mouse mAbs
  • how can this reaction be prevented
A
  • Mouse mAbs have protein sequences that differ from naturally occurring human antibodies
  • When administered to humans, mouse mAbs may be recognized
    as foreign by the human immune system
  • Causing dangerous immune reactions
  • Resulting in destruction and removal of the mouse mAbs - rendering the therapy ineffective
  • Recombinant DNA technology can be used to modify mouse
    mAbs, enhancing their resemblance to human antibodies and
    reducing the risk of adverse immune reactions
  • Recombinant DNA is made by combining DNA from two or more sources
  • DNA encoding the mouse mAb is merged with human antibody producing DNA –> this recombination results in a partially mouse, partially human mAb
17
Q

What are the types of mAb in recombinant antibody engineering?

A
  1. Mouse mAb
    e.g. Zevalin
    (non-Hodgkin’s lymphoma)
  2. Chimeric mAb
    ~66% human
    Mouse variable region +
    human constant region
    e.g. Remicade
    (inflammatory diseases)
  3. Humaized mAb
    >90% human
    Mouse antigen-binding site +
    human origin for remaining mAb
    e.g. Herceptin
    (breast cancer)
  4. Human mAb*
    100% human
    e.g. Humira
    (inflammatory disease)
  • Fully human antibodies can be created using methods which included human hybridomas, transgenic
    mice (mice engineered to produce human antibodies)
18
Q

Antibody drug case study: treatment of snakebite

State the context of snakebites

  • how big of an unmet medical need
  • how many deaths and disabilities?
  • what age groups are most effected?
  • what region and SEC?
  • when and how are people effected?
  • what did the WHO classify snakebites as
  • what is the toxic part in snakebites?
A
  • Context: snakebite
  • Major global health need (unmet medical need)
  • > 100,000 deaths each year
  • > 400,000 permanent disabilities each year
  • Half: women and children
  • Impact: low- and middle-income sub-Saharan Africa and Asia
  • When/how? People are bitten working in fields, as they fetch drinking water, while sleeping in houses at night, when going to school, or even just walking to an outdoor toilet
  • World Health Organization: 2017, designated Snakebite as a Neglected Tropical Disease
  • Snakebite toxic component(s): venom
19
Q

what is a traditional treatment for snakebites?

A
  • Antibody-based antivenom therapy (polyclonal antibodies)
    –> From animals (immunize horses and cows to produce antibodies)
  • This approach: used for >100 years
20
Q

what are two types of venemous snakes?

A

King cobra (O. hannah)

Black mamba (D. polylepis)

21
Q

what are the kinds of snake venom peptides/toxins/
proteins that predominate in different species?

A

specifically the 3FTx, three finger toxin

help narrow down what to make a drug against as this is present in most venoms

22
Q

what is the receptor target of the snake toxin?

A
  • Target of the snake toxin: human muscle-type nicotinic acetylcholine
    receptor (nAChR) at neuromuscular junctions
  • When the toxin binds to this receptor, it interferes with the normal signaling process between nerve and muscle cells, causing paralysis and death by asphyxiation (when muscles involved in breathing are paralyzed)
23
Q

explain possible treatment of antibodies to treat snakebites

feb 21, 2024

A
  • using synthetic antibodies to treat a snakebite
  • broadly-neutralizing human antibodies directed against snake peptide (3-finger long chain family of snake peptides)
24
Q

describe the preclinical results of how synthetic antibodies are used to protect mice from snake venom death.

the experimental and rescue experiments

A
  • Usually when the mice is bit by a snake, it dies within the hour

experiment:
Timing:
* Inject mice with 1 of 3 different kinds of snake venom
* Treat with synthetic antibody (95Mat5) or commercial antivenom that had been
pre-incubated with venom
–
D. polyepis bites
- traditional antivenoms, not the best - extend the life of the mice by a couple hours but they still die.
- new synthetic antivenom = 100% survival rate

O.Hannah bite
- traditional antivenoms, not the best - extend the life of the mice by a couple hours but they still die.
- new synthetic antivenom = 12 hr extended life

Rescue experiment:
Timing:
* Inject mice with 1 of 2 different kinds of snake venom
* Treat with antibody 0, 10 or 20 min after venom (“rescue” experiment, E,F)
* Measure survival up to 24 hours
–
N. Kauthina rescue and D. polypersis rescue
- 100% rescue rate after bitten by snake

25
Q

what are the summary of results for the snakebite preclinical experiment

A
  • Collectively, these data show that a single monoclonal antibody can
    provide broad preclinical protection against 3FT-L venoms, and
    exhibits superior efficacy compared to commercially available antivenom.
  • Structural characterization of the synthetic antibodies indicate that they mimic the interaction between the venom toxin and the human nicotinic acetylcholine receptor (provide info about target)
26
Q

what are the impacts of the snakebite case study (3)

A
  • Important first step in development of a monoclonal antibody
    therapy – a universal antivenom
  • Effectively neutralizes one of the most diverse and toxic components
    of snake venom
  • Potential global impact
27
Q

what are issues with biologics (7)

A
  • Complexity
  • High specificity
  • Selectivity often > small molecules due to large surface
  • Toxicity generally < small molecules due to selectivity
  • Potential for immunotoxicity
  • Monoclonal antibodies – long half-life
  • High cost
28
Q

are biologic drug approvals rising?

A

yes! 20 percent increase from 1998 to recent years 2016-2021

29
Q

what are common characteristics of a speciality drug?

A

Common characteristics of a specialty drug:
* High cost (>$750 per month)
* Requires specialized handling, administration and/or monitoring
* Used to treat complex or rare diseases
* Often a biologic, rather than a traditional small molecule drug

30
Q

are speciality drugs profitable? how will they affect the future sales? how many speciality drugs are currently represented in the pipeline?

A

yes. Specialty drugs are among the most profitable drugs (worldwide sales data)

Specialty drug predicted to dominate future sales and development pipeline
- The top 10 best-selling medicines globally in 2025 are predicted to be mostly specialty drugs

  • Specialty medicines represent >60% of all drugs currently in the development pipeline
31
Q

why are speciality drugs so expensive? (3)

A

Potential explanations for the high costs of specialty drugs:
* Increased manufacturing costs compared to conventional drugs
* Covering development costs and provide return on investments
* Specialty drugs often have small target patient populations
–> With a relatively low volume of sales, the cost-per-patient must be higher for the drugs to be profitable

32
Q

explain remicade an example of a speciality drug

  • type of drug
  • indication
  • administration
  • cost
A

type of drug: monoclonal antibody (biologic)

indication: Used to treat autoimmune disease (inflammation that results from the body’s own defense system attacking the skin, joints, intestines, or stomach)

administration: Administered intravenously, typically in a hospital or clinic

cost: Approximately $28,000 to $30,000 per year* CAD

33
Q

explain how remicade works in action with TNF-alpha

A
  • Autoimmune disease result from the immune system attacking the body’s own tissues and is often associated with increased inflammation
  • Tumor necrosis factor alpha (TNF-α) is a key factor in regulating inflammation
  • Remicade is a mAb that targets TNF-α
  • By inactivating TNF-α, the inflammatory process can be significantly diminished
  • Remicade can reduce the signs and symptoms of certain autoimmune diseases
34
Q

how successful is remicade on the market

A
  • Remicade is one of the top selling drugs in the world
  • In 2014, Remicade recorded sales of nearly $10 billion worldwide and $800 million in Canada
  • Patent protection for Remicade expired in 2012
  • Due to the success of Remicade, other infliximab products were developed and marketed
35
Q

what are generics in SMDs and biosimilars in biologics?

A

Small molecule drugs:
innovator SMDs:
New SMD against new target

generics:
Contains the same active ingredient as innovator SMD
Chemically equivalent & bioequivalent

biologics:
innovator biologics: New biologic against new target

biosimilars: Biologic product that is similar to the innovator
Comparable quality, clinical efficacy and safety

36
Q

how are biosimilars and generics different?

A
  • Generics are considered “bioequivalent” and interchangeable with the reference product - biosimilars are only similar and not interchangeable
37
Q

why is it challenging to create a biosimilar that is an exact replica of the innovator biologic?

A
  • Biologics are large and complex molecules and they are complicated to develop and manufacture
  • Manufacturers of the innovator drugs are not required to share their original formulas (e.g., materials, equipment, and processes used to create the product)
  • Any slight alteration in formula could result in structural changes to the product with potential for different clinical effects
  • Similar to snowflakes, biosimilars from different manufacturers differ from their reference innovator biologic and from each other
38
Q

comparison between generic, biological, biosimilar drugs

cost, time, patients

A

much more expensive to create a biologic than biosimilar then generic

less time to make the others than the biologic

less patients required for testing on generics and biosimilars than biologic

39
Q

what is the future of biosimilars like?

A
  • The availability of biosimilars may increase affordability and access to biologics
  • An influx of biosimilar submissions for marketing authorization is expected
  • Today, there are numerous biosimilars development programs underway and multiple programs for each of the top selling biologics

PCL102 (19 decks)

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