mAbs

Question 1

first mAb to be approved

Answer 1

muromonab-CD3

Question 2

examples of mAbs through development

Answer 2

1. human Fc, mouse variable: infliximab, rituximab
2. only CDR mouse: omalizumab, alemtuzumab
3. human: adalimumab

Question 3

alemtuzumab action

Answer 3

binds to CD52, only on mature lymphocytes (not undifferentiated) and targets them for destruction

Question 4

research ongoing to improve mAbs focuses on:

Answer 4

1. bispecific
2. engineered improvement of coupling
3. conjugation with toxins
4. improved pharmacokinetics

Question 5

bispecific antibody example

Answer 5

catumaxomab - binds epithelial cell adhesion molecule (tumour) and CD3

Question 6

engineered improvement of antibody-NK cell coupling example

Answer 6

• mogamulizumab (anti-CCR4), anti-cancer
• fucosylated Fc causes displacement of oligosaccharide coupled to Asn162 of FcgammaRII, so increased distance and reduced affinity

Question 7

conjugation of toxins to mAbs example

Answer 7

trastuzumab emtansine = Herceptin (disrupts signalling, targets for ADCC) + DM1 (binds to tubulin and prevents polymerisation)

Question 8

how to improve pharmacokinetics

Answer 8

• increase affinity of IgG for FcRn at physiological pH
• make peptide scaffold smaller or use bicyclic peptides
• use heavy chains only