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MH3050 Advances in Translational Medicine > Advances in Monoclonal Antibody Therapy > Flashcards

Advances in Monoclonal Antibody Therapy Flashcards

1
Q

Small molecule drug

A
  • Low MW
  • Chemically synthesised (defined chemical reactions)
  • Simple, well defined structure
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2
Q

What are small molecules known as?

A

The pillars of traditional medicine

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3
Q

Examples of small molecule drugs targets

A

Extracellular proteins
Intracellular receptors
In cytoplasm, nuclei, CNS

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4
Q

Examples of small molecule drugs

A

Aspirin
Penicillin
Paracetamol
Lipitor (Atorvastatin)

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5
Q

Biological molecule

A
  • High MW
  • Derived from living organisms (manufactured)
  • Large, complex, dynamic structure
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6
Q

Uses of large biologics

A
  • Therapeutic proteins (peptides, antibodies)
  • Nucleic acid based therapies (RNAi, gene therapy/editing)
  • Blood components
  • Cellular therapies (e.g. CAR T-cell therapy)
  • Tissue therapies (allogenic transplants)
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7
Q

50% of biologics marketed today are?

A

Monoclonal antibodies (fastest growing class of drugs)

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8
Q

Monoclonal antibody

A

An example of a biologic

High specificity, allowing the stimulating of the immune system to attack certain antigenic cells

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9
Q

What is the large biologic that is the 2nd best selling drug (2021)? What is it used for?

A

Humira (mAb)

  • Autoimmune disease treatment (rheumatoid arthritis, psoriatic arthritis, Crohn’s, psoriasis)
  • Forecasted to be replaced by Keytruda by 2024 (mAb for cancer immunotherapy)
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10
Q

Small molecules vs Biologics

A

Small mol: low MW, simple structure, independent of manufacturing process, identical copies possible, well-defined, stable, non-immunogenic

Biologic: high MW, complex structure, defined by exact manufacturing process, identical copies impossible, can’t be characterised completely, unstable, immunogenic

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11
Q

Advances in biotechnology enabled?

A

Synthesis of biological molecules (proteins) in microorganisms & other living cells (via recombinant DNA technology)

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12
Q

Key areas for mAb use

A
  • Immunotherapy
  • Inflammatory diseases
  • Autoimmune diseases
  • CVD
  • Oncology
  • Neurodegenerative diseases
  • COVID-19
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13
Q

Briefly discuss mAb therapy

A
  • Very specific
  • Immunotherapy
  • Uses mAbs to bind monospecifically to certain cells or proteins
  • Stimulation of patient’s immune system to attack certain cells
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14
Q

Antibody functions

A
  • Neutralisation
  • Agglutination
  • Precipitation
  • Complement activation
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15
Q

How do mAbs work?

A
  • Variable region of antibody binds to a single antigen
  • Specific binding
  • mAbs are useful for highly targeted therapeutic administration
  • Minimises adverse off target side effects
  • Useful for delivery of toxic drugs
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16
Q

True or False: The host’s immune system produces long-term Abs after short-term mAb drug administration

A

True

17
Q

The first reliable source of mAbs

A

Immunotherapy, 1970s, Hybridoma technology

  • Orthoclone 1986 - limited organ transplant rejection
  • Can take the hybridoma out of the mouse & modify it → develop it into a mAb
18
Q

The biggest manufacturing problem associated with mAbs

A

Low stability

19
Q

Discuss Keytruda (Pembrolizumab)

A

Humanised mAb used in cancer immunotherapy
- Binds specifically to PD1

  • Few severe adverse events (5%: fatigue, rash, dry mouth)
  • Can be combined with targeted and untargeted drugs
    (i) Chemotherapy
    (ii) Radiotherapy
    (iii) Immune modulators
20
Q

What is PD-1?

A

PD1 = programmed cell death protein 1
- PDL-1: transmembrane protein of cancer cells, which prevents PD-1 from identifying it & the immune system from killing the cancer cells

PD1 blockade: ↑ T-cell mediated anti-tumour immunity, inhibits T-cell PD1/tumour cell PD1 interaction, potential treatment strategy

21
Q

Is cytotoxic activity associated with Keytruda?

A

Cytotoxic activity occurs when Fc receptors are engaged and the complement system is activated. This does not occur in Keytruda → no cytotoxic activity

22
Q

Keytruda and metastatic melanoma

A

median survival <12 months

  • Assoc. with genetic mutations
  • Inhibitors - 10% response
  • Conventional chemotherapy ineffective
  • Few treatment options
  • Keytruda - for non-responders/relapse
  • 1st trial saw up to 52% overall response rate
  • Overall response rates consistently higher than chemotherapy
  • Progression free survival higher than chemo
  • Improved safety profile vs chemo & other mABs (ipilimumab)
  • FDA approved 2014
23
Q

Keytruda and non-small cell lung cancer (NSCLC)

A
  • NSCLS: median survival ~10 months
  • Platinum based chemotherapy (first line treatment)
  • Few other options
  • 1st PD1 blockade trial: Nivolumab
  • ↑ overall response rate to 20% compared to 9% seen with chemo
  • Keytruda - overall survival superior to chemotherapy
  • ↑ when >50% of tumour cells expressed PDL1
  • ↑ progression free survival
  • Fewer adverse events
  • FDA approved 2015
24
Q

Keytruda and lymphoma

A

↑ PDL1 expression in Hodgkin Lymphoma

  • Good response to PD1 blockade
  • Nivolumab - 87% overall response rate
  • Keytruda for non-responders/relapse/ineligible for transplant
  • Poor response in early studies/trials
  • Toxicity (dosages v important) & SAEs
  • 2mg/kg every 3 weeks - complete response, no toxicity
  • Lower doses could be more useful for lymphoma treatment
25
Q

mAbs vs standard cancer therapies

A

mAbs: ~35 FDA approved, restricted admin (I.V. injection or infusion), unstable, highly targeted ‘tailored’ approach (single antigen), few side effects, takes longer for mAb to work (pseudoprogression), long term efficacy & protection, low cytotoxicity

Chemo: ~150 approved, unrestricted admin, stable, untargeted, impairs ca. cell’s ability to replicate, many side effects, immediate effect, treatment effects last only as long as drug remains in system, high cytotoxicity

26
Q

Why do we see a lot of relapses with cancer?

A

If all of the cancer cells are not killed by the chemo, they will begin to replicate again

27
Q

Successful development of mAb requires

A
  • Identification & creation of a selective, potent target molecule
  • Humanisation of sequences
  • Affinity maturation
  • Fc engineering (modulation of effector functions)
  • Engineering to address biophysical liabilities
28
Q

the most commonly used animals in mAb development

A

Non-human primates (NHPs)

29
Q

Challenges associated with NHPs

A
  • Critical differences in NHP and human physiology
  • Imperfect translation of study results to human safety effectiveness (due to potential differences in target molecule activity)
  • Ethical concerns
30
Q

Solution to NHP challenges

A

Mouse target knockout phenotypes

  • In vitro & in silico (system pharmacology, modelling)
  • Reduces animal use
  • Improves safety prediction
  • Improves overall mAb development process
  • Reduces challenges of interspecies translation
31
Q

mAbs are selected based on

A
  • Affinity
  • Potency
  • Efficacy
  • Biological activity
32
Q

Significant challenges associated with manufacturing mAbs

A
  • Poor expression
  • Solubility
  • Cross reactivity (with different molecules)
  • Poor pharmacokinetic profiles
  • Product stability
    (due to molecule complexity)
33
Q

Why are mAbs so unstable?

A

Because they have to be highly concentrated (due to FDA regulations - volume of SC injection must be <1.5ml)

34
Q

Disadvantages of highly concentrated mAbs

A
  • Reduced volume for mAb molecules - crowding
  • Formation of irreversible non-covalent protein aggregates
  • Increased viscosity (challenging to fill product)
35
Q

Solutions for product stability

A

Addition of excipients i.e. sugars

  • Prevent formation of irreversible aggregates
  • Sugars interact with H2O molecules, not proteins
  • Protein molecules can maintain native conformation
  • Reduces aggregates

mAb efficacy linked to structural, conformational & chemical stability

36
Q

Why is stability management critical?

A

Reduces physical/chemical degradation

37
Q

Stabilisation strategies

A
  • pH optimisation
  • Effective buffer components
  • Surfactants - stabilise protein molecules (making them less susceptible to these stresses that can cause physical & chemical degradation)
    i. e. sugars and polyols - have antioxidant & cryoprotective properties
38
Q

Benefit of Fc fusion proteins

A

i.e. Fusion of coding sequence for Fc region of mAb with coding sequence of another protein
Proteins/peptides have short half lives - Fc fusion extends half life

MH3050 Advances in Translational Medicine (14 decks)

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