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PHAR 211 > Biologic Drug Development > Flashcards

Biologic Drug Development Flashcards

1
Q

What is the relevance of antibodies in the pharmaceutical industry?

A

Antibodies are versatile drugs and dominate the pharmaceutical market (by revenue)

They are expensive for consumers, but are easier for manufacturers to turn a profit

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2
Q

What is the central dogma of molecular biology?

A

DNA –(transcription)–> RNA –(post-transcription modification)–>mRNA–(translation via ribosome)–>Protein

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3
Q

What happens to hydrophobic or hydrophillic amino acids in a polypeptide chain?

A

Hydrophobic amino acids are internal, while hydrophillic amino acids are external

This type of organization results in globular structures

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4
Q

What are the four levels of protein structure?

A
  1. Primary structure
  2. Secondary structure
  3. Tertiary structure
  4. Quaternary structure
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5
Q

In general, how do antibodies work?

A

Antibodies can target individual proteins and modulate structure and function

Binding is mediated by CDR loops

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6
Q

What are the components of humoral immunity?

A

B lymphocytes are the main cells involved in humoral immunity

B cell (with antibodies on cell surface and activated by helper T-cells)

Antibody-secreting B cell (release free antibodies)

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7
Q

What are the components of cell-mediated immunity?

A

T-cells bind to antigen-presenting cells and either release cytokines or kill infected cells

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8
Q

What is the basic structure of antibodies?

A

Heterotetramer with two identical light chains and heavy chains.

Fab portion is important for antigen binding

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9
Q

What are some effector functions of antibodies?

A
  • Inactivates, prevents binding of pathogens and toxins to cells
  • Induce phagocytosis or lysis
  • NK cell-induced apoptosis (useful in cancer)
  • Indice degranulation
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10
Q

What are the different types of anti-cancer antibodies?

A
  1. Tumour-specific IgG
  2. Angiogenesis inhibition
  3. Checkpoint blockade
  4. Radioimmunotherapy
  5. Antibody-drug conjugate therapy
  6. Bispecific antibody (BiTE therapy)
  7. CAR T-cells

review slide 12

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11
Q

Why are antibodies specific to a specific antigen?

A

Antigen and antibody binding sites need to be structurally and chemically compatible

CDR loop confirmations enables binding to diverse antigens

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12
Q

How is antibody diversity generated?

A

Exon mix and match in the IgH locus results in the diversity of CDR loop confirmations

see slide 15

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13
Q

In geneal, how are antibodies manufactured?

A
  • An antigen is injected into mouse
  • Mouse creates antibodies in B cells
  • These antigen-producing B cells are fused with a tumour cell to generate a viable hybridoma
  • These hybridomas will contnually generate monoclonal antibodies against the original antigen
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14
Q

What is a major issue of murine (sourced from mice) antibodies?

A

They are immunogenic

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15
Q

Are humanized antibodies also immunogenic?

A

There will be a reduced immune attack and foriegn body detection responses with humanized aantibodies vs. murine antibodies

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16
Q

How does Xenomouse (Trangenic mice) technology work?

A

Antibody genes in mice are replaced with human genes

Subsequent human antibodies are inserted into B cells and fused with tumour cells to form hybridomas

The hybridomas produce fully human monoclonal antibodies

17
Q

What is phage display?

A

M13 bacteriophage (antibodies are expressed on the phage surface as fusion to coat proteins)

Direct site mutagenesis is used to make antibody variants

Libraries of 10^10 variants can be generated and screened

18
Q

How does a naive antibody library respond to a novel antigen?

A

Trial and error process of testing native antibodies against antigens

19
Q

What are the four methods for making antibodies?

A
  1. Mouse hybridoma
  2. Phage display
  3. Transgenic mouse
  4. Single B cell

slide 22

20
Q

What are the types of antibiotic fragments used in phage-display?

A
  • Full IgG
  • Fab
  • scFv
  • VH/VHH

slide 27

21
Q

What is the favoured antibody type for solid tumour therapies?

A

scFV has improved penetration into solid tumours

22
Q

Do antibody-based drugs have a lower success rate for FDA approval?

A

No, success rates are almost 3x compared to small molecules (23% vs. 7%)

23
Q

What is the most common type of approved antibody?

A

Canonical antibody (full IgE molecule alone)

24
Q

Are most antibodies designed to target unique targets?

A

No, 45% of antibodies are targeted against the top ten targets

PD1/PDL1, CD20, TNF, HER2 are some common targets for antibodies

25
Q

What is an examples of a canonical antibody?

A

Bevacizumab

Humanized murine mAb targeting VEGF A (inhibition of angiogenesis)

26
Q

How was bevacizumab humanized?

A

CDR regions from murine antibody were grafted onro a human Fab fragment sequence

27
Q

What is the advantage of engineering Fc fragments for antibodies?

A

They help the antibody evade degradation

slide 35

28
Q

What is the role of a linker in antibody drug conjugates?

A

They connect the antibody to the payload

Payload release is dependent on the linker and it can be triggered by tumour specific factors

29
Q

What is the payload in antibody drug conjugates?

A
  • Can be active drug or radioactive material
  • Ensures low impact on non-targeted tissues (narrow window)
30
Q

What are some functions of bispecific antibodies?

A
  1. Bridging cells (in-trans): T-cell and antigen brought into proximity
  2. Receptor inhibition (in cis): prevent HER2 dimerization
  3. Receptor activation (in cis): bring together two cell surface proteins and enhance activation
  4. Co-factor mimetic
  5. Piggybacking (use receptors for other drugs, to help import across BBB)

slide 39

31
Q

What is a quadroma?

A

It is the viable result of the fusion of two hybridomas

From this process, a bispecific antibody can be generated (quadroma contains CDR regions for different antibodies)

32
Q

What is knob-in-holes technology in the context of bispecific antibodies?

A

These mutations prevent/reduce homodimerization of heavy chain due to steric hindrance (light chain cross over can still happen)

This increases the proportion of desired bispecific antibodies

33
Q

What is the use of Cross-Mab technology in the context of bispecific antibodies?

A

Light chain crossover is prevented by fusing the light chain with the heavy chain

34
Q
A

PHAR 211 (18 decks)

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