therapeutic antibodies

Question 1

what does adcc stand for

Answer 1

antibody dependent cellular cytotoxicity

Question 2

4 mechanisms of mono-clonal antibody-induced cytotoxicity

Answer 2

1. recruitment of human immune function
   - adcc and phagocytosis
   - complement mediared lysis
2. direct cytotoxic or down regulatory effect
   - blockade of gf complement
   - induction of apoptosis
3. delivery of cytotoxic conjugate
   - chemotherapeutic drug
   - enzyme
4. indirect induction of immune response to tumour
   - stim of host cellular response
5. bifunctional effects
   - bispecific antibodies cross-link target and cytotoxic effector cells

Question 3

what are antibody drug conjugates

Answer 3

cytostatic or cytotoxic drugs can be conjugated to monoclonal antibodies

conjugation of a mAb ensures target delivery

Question 4

what is conjugation

Answer 4

the process of genetic transfer between bacterial cells that requires direct contact between cells

Question 5

what is ADEPT

Answer 5

antibody directed prodrug therapy

the prodrug targets the enzyme to reduce tumour cell

Question 6

what are bispecific antibodies

Answer 6

when an effector cell causes adcc or phagocytosis

being used to retarget t cells to tumours or blockade two receptors

Question 7

3 clinical uses of mAbs

Answer 7

diagnostic imaging and therapy of cancer

treatment of infections

induction of immunosuppression

Question 8

5 potential targets of mAbs in cancer therapy

Answer 8

tumour associated blood vessels
vascular growth factors
diffuse malignant cells
tumour within a solid tumour 
tumour associated stroma

Question 9

what is rituximab

Answer 9

chimeric human igG1 that binds to Cd20 on normal and malignant preB and mature Bs
induces adcc and complement mediated lysis
triggers apoptosis
used to treat b cell non-hodgkins lymphoma and RA
potential use in malignancies

Question 10

what is trastuzumad (herceptin)

Answer 10

humanised igG1
binds to human epidermal growth factor receptor 2 (HER2)
used to treat patients with metastatic breast cancer
kills tumours by triggering adcc via fc receptors
herceptin treatment follows chemo

Question 11

what is cetuximab (erbitux)

Answer 11

chimeric human igG produced in mouse sp2/0 cells
binds egf receptor
used to treat metastatic colorectal cancer and squamous cell carcinoma of head and neck
very expensive treatment
some patients have allergic reaction during infusion

Question 12

what is the issue with cetuximab and people who have pre-existing antibodies for a1,3-galactose

Answer 12

allergic reaction
generates a foreign epitope
initial antibody production may have been caused by tick bites or reaction to red meat

Question 13

where does cetuximab bind to and what is the signalling pathway involved

Answer 13

binds to FcER1 on mast cells
causes crosslinking of receptors
lyn and srk kinases are phosphorylated
histamines, prostoglandins and leukotrienes are released

Question 14

3 ways to avoid allergic reactions to a1,3-galactose on mAbs

Answer 14

1. screen individuals for presence of specific igE
2. produce mAbs that have n linked sugars in fab regions in cho cells rather than sp2/0 or nso cells
3. in future select mAbs that lack n linked sugars in fab regions

Question 15

what are immune check points

Answer 15

checkpoints that turn the signal up or down

mAbs against checkpoints are showing promise in treatment of cancers such as melanomas

Question 16

immune check point priming phase

Answer 16

in lymph node
- t cells initiate immune response by recognising antigenic peptides presented by mhc
- additional co-stim signals are needed for effector responses
ctla-4 interacts with b7 to inhibit t cell activation
mAbs interact with b7 to stop inhibition

Question 17

immune check point effector phase

Answer 17

in the periphery
- t cell recognise antigenic peptides presented by mhc on cancer cells
- pd-1 inhibits effector cell activity within tissues
-pdl1 is expressed on the tumour micro environ
mAbs to either pd1 or pdl11 stop inhibition
allows t cell to mediate or trigger the killing mechanisms against tumour cell

Question 18

ipilimumab

Answer 18

human igg1 against ctla4
blocks ctla4 activit so anti tumour t cell response is generated
approved treatment for adv melanoma

Question 19

mogamulizumab

Answer 19

against chemokine receptor type 4
used for patients with relapsed or refractory ccr4 psotoive t cell lukaemia
humanised igg1

Question 20

glycans

Answer 20

glycan structure has a big effect on of effector func and immunogenicity

Question 21

how are pro-inflam cytokines produced in RA

Answer 21

joint inflam caused by infiltration of synovium by activated self-reactive helper t cells

Question 22

inflam cytokines involved in ra

Answer 22

chronic production of INFa, IL-1, IL-6
activates synovial fibroblasts, osteoclasts and chondrocytes
releases matrix metalloprotienases which leads to the destruction of cartilage and bones

Question 23

infliximab

Answer 23

chimeric human igg1, binds to human TNFa
blocks TNFa ability to induce:
- proinflam cytokines il1 and il6
increased leukocyte migration 
increased neutrophil and eosinophil activity
acute phase protein 
treats ra, chrons and psoriasis

Question 24

tocilizumab

Answer 24

anti il6r
humanise digg1
approved for ra

Question 25

omalizumab

Answer 25

humanised igg1 binds ige fc
blocks ige binding FcER1, prevents symptoms of allergic response
treats hayfever and allergic asthma

how it works:
binds ige
decreased expression of high affinity receptor on mast cells, basophils and eosinophils
decreases mediator release from cells
decreases allergic inflammation
prevents exacerbation of asthma and reduces symptoms
v expensive drug

Question 26

mepoluzimab

Answer 26

humanised mab agains Il-5
blocks eosinophil production
approved add on to asthma treatment

Question 27

TGN1412

Answer 27

anti cd28
humanised igg4 binds cd28 on t cells
intended to treat b cell chronic lymphocytic leukaemia and ra
all recipients experienced cytokine release symdrome . - side effects are fever swelling of skin and mucous membrane and vomitting

in animals - only reg t cells are actived
in humans both helper and t regs activated causing mass cytokins storm and flood on inflam molecules