therapeutic antibodies Flashcards
what does adcc stand for
antibody dependent cellular cytotoxicity
4 mechanisms of mono-clonal antibody-induced cytotoxicity
- recruitment of human immune function
- adcc and phagocytosis
- complement mediared lysis - direct cytotoxic or down regulatory effect
- blockade of gf complement
- induction of apoptosis - delivery of cytotoxic conjugate
- chemotherapeutic drug
- enzyme - indirect induction of immune response to tumour
- stim of host cellular response - bifunctional effects
- bispecific antibodies cross-link target and cytotoxic effector cells
what are antibody drug conjugates
cytostatic or cytotoxic drugs can be conjugated to monoclonal antibodies
conjugation of a mAb ensures target delivery
what is conjugation
the process of genetic transfer between bacterial cells that requires direct contact between cells
what is ADEPT
antibody directed prodrug therapy
the prodrug targets the enzyme to reduce tumour cell
what are bispecific antibodies
when an effector cell causes adcc or phagocytosis
being used to retarget t cells to tumours or blockade two receptors
3 clinical uses of mAbs
diagnostic imaging and therapy of cancer
treatment of infections
induction of immunosuppression
5 potential targets of mAbs in cancer therapy
tumour associated blood vessels vascular growth factors diffuse malignant cells tumour within a solid tumour tumour associated stroma
what is rituximab
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
what is trastuzumad (herceptin)
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
what is cetuximab (erbitux)
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
what is the issue with cetuximab and people who have pre-existing antibodies for a1,3-galactose
allergic reaction
generates a foreign epitope
initial antibody production may have been caused by tick bites or reaction to red meat
where does cetuximab bind to and what is the signalling pathway involved
binds to FcER1 on mast cells
causes crosslinking of receptors
lyn and srk kinases are phosphorylated
histamines, prostoglandins and leukotrienes are released
3 ways to avoid allergic reactions to a1,3-galactose on mAbs
- screen individuals for presence of specific igE
- produce mAbs that have n linked sugars in fab regions in cho cells rather than sp2/0 or nso cells
- in future select mAbs that lack n linked sugars in fab regions
what are immune check points
checkpoints that turn the signal up or down
mAbs against checkpoints are showing promise in treatment of cancers such as melanomas
immune check point priming phase
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
immune check point effector phase
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
ipilimumab
human igg1 against ctla4
blocks ctla4 activit so anti tumour t cell response is generated
approved treatment for adv melanoma
mogamulizumab
against chemokine receptor type 4
used for patients with relapsed or refractory ccr4 psotoive t cell lukaemia
humanised igg1
glycans
glycan structure has a big effect on of effector func and immunogenicity
how are pro-inflam cytokines produced in RA
joint inflam caused by infiltration of synovium by activated self-reactive helper t cells
inflam cytokines involved in ra
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
infliximab
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
tocilizumab
anti il6r
humanise digg1
approved for ra
omalizumab
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
mepoluzimab
humanised mab agains Il-5
blocks eosinophil production
approved add on to asthma treatment
TGN1412
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
