The changing face of therapeutics Flashcards

1
Q

What are monoclonal antibodies?

A

members of the Ig superfamily
IgG 1-4 with different constant domains

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2
Q

Which mab is mainly used in therapies

A

IgG1 or 3
IgG 1 has good antibody binding

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3
Q

How many types of monoclonal antibodies are there?

A

4 types
Murine (-omab)
Chimeric (-Ximab)
Humanised (-zumab)
Human (-umab)

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4
Q

What are the mechanisms of therapeutic antibodies?
Give an example drug for each mechanism

A

Cytokine & growth factor blockade
Ligand blockade
Receptor blockade
Receptor downregulation
Depelting and signalling antibodies
Weaponised antibodies
Bispecific antibodies

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5
Q

Neutralising and blocking antibodies

A

Ligand blockade: infliximab - a recombinant humanized monoclonal antibody hand binds soluble TNF alpha
Receptor blockade: Tocilizumab - a recombinant humanized monoclonal antibody IL-6 receptor inhibitor used to treat autoimmune conditions
Receptor downregulation: Efalizumab - a recombinant humanized monoclonal antibody binds to CD11 receptors on T lymphocytes

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6
Q

Depleting and signalling antibodies:

A

Antibody-dependent cell mediated cytotoxicity (ADCC)
Antibody-dependent cellular phagocytosis (ADCP)
Complement-dependent cytotoxicity (CDC)

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7
Q

Explain the neonatal fragment crystallisable (Fc) receptor FcRn

A

Antibodies (e.g. IgG and albumin) have long plasma half lives
Ingested via pinocytosis
Once ingested they bind to the neonatal fragment crystallisable receptor (FcRn)
But only binds to the FcRn when its acidic (pH 5.0-6.5) [not in its physiological pH 7.4]
acidification = FcRn binds IgG (and albumin)
Retained within endosome
FcRn bound IgG os transported back to the plasma membrane
Vesicle exocytosis =IgG is released into circulation

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8
Q

What is Myasthenia Gravis?

A

Autoimmune disease caused by IgG against alpha 1 subunit of the nicotinic acetylcholine receptor in neuromuscular junctions

Causes loss of motor activity
Initial stages treat with cholinesterase inhibitors
No disease modification

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9
Q

State a drug treatment for Myasthenia Gravis

A

Efgartigimod (VYVGART)

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10
Q

Efgartigimod MOA

A

FC Frgament (pH independent to FcRn) > binds to receptor > Lowers IgG and blocks IgG transfer across barriers

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11
Q

Weaponised antibodies (oncology)

A

-Radioactive element delivers a short range burst of radiation to cells targeted by the antibodies

or

-Chemical linkage to a bacterial toxin

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12
Q

Bispecific antibodies

A

Multiple functionally different binding domains that allow for interaction with two target antigens

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13
Q

State the strengths and weaknesses of antibodies

A

Strengths:
High success rate
Well tolerated
Generally specific (less off target effects)

Limitations:
Expensive with high production costs
Limited penetration to CNS
Cannot be administered orally

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14
Q

What are the benefits of using nanobodies?

A

Robust binding molecules (more potent)
Chemical and thermal stability
Better penetration into tissues and organs

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15
Q

State the types of dysfunctional proteins

A

Poor translation
Truncated protein
Protein that doesn’t go where its supposed to
Protein does not function
Excess protein

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16
Q

What is spinal muscular atrophy (SMA)

A

SMN1 encodes for survival motor neurone protein 1 - essential for nerve maintenance
Sufferers inherit two copies of a missing or faulty (mutated) SMN1 gene

Motor neurones wither and die

17
Q

DNA therapeutics (Vectors)

A

Replacing therapeutic proteins when delivered to the nuclei of patients cells

Vectors > lentivirus, adenovirus
Eludes the hosts immune defences
(Viruses are self-inactivating and replication-deficient)

18
Q

Genomic editing

A

Adding, removing or altering genetic material

Utilize nucleases are guided by DNA binding proteins or RNA to cleave genomic DNA

Zinc finger nucleases
Transcription activator-like effector nucleases (TALENs)
Clustered regularly interspaced short palindromic repeats (CRISPR) and associated proteins (Cas)

19
Q

What are the 2 different Gene editing systems?

A

Clustered regularly interspaced short palindromic repeats-CRISPR = single-guide RNA carries DNA cutting enzyme Cas9 to target sites

Transcription activator-like effector nucleases -TALEN = TALEs are fused with the DNA scissors, Fok1

20
Q

RNA therapeutics +example
(mRNA delivery)

A

SARS-COV2 Vaccine
Pfizer/Biontech = mRNA for spike protein in oily capsule (nanoparticle)

21
Q

What are Antisense Oligonucleotides?
What are the 2 types?

A

short single stranded DNA phosphorothioate DNA, RNA analogs, complementary to a certain region of RNA they are meant to target

-Alter RNA and reduce, restore or modify proteins expression

2 types:
RNase H-dependent ASO-provides (good for excessive protein = knockdown)

RNase H-independent ASO-provies steric block = changes expression of proteins by inhibiting/preventing splicing machinery

22
Q

Exon skipping

A

Alisense oligonucleotides can target splice sites leading to exon skipping or shifting the ratio between existing splice forms

23
Q

Small interfering RNAs (siRNAs)

A

Small non-coding RNA duplexes that originate from precursor siRNAs
Effective at silencing gene products

24
Q

Premature stop codon

A
  • Nonsense mutations result in loss of function characteristics

Drugs can prevent premature stop codons
E.g. in cystic fibrosis readthrough agents can be used

25
Q

Stem cells (Extra learning ??)

A

Remove induced pluripotent stem cells (IPSCs)
treat with gene editing technology
Apply DNA alkylating agent for the dividing cells
Infuse with modified stem cells

Sickle cell aneamia treatment

26
Q

What are antisense oligonucleotides?

A
27
Q

What is CRISPR/CAS9

A