Antibody engineering

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  • Created by: Biokid373
  • Created on: 22-05-22 15:08
What are rituximab and alemtuxumab designed for?
Cancer
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what does Rituximab target?
CD20
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What does Alemtuzumab target?
CD52
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What does the Fc region of an antibody do?
interacts with effector immune cells
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What does Rituximab treat?
B cell lymphoma
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Where is CD20 expressed?
on the surface of B cells
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what is an anti-idiotype?
Anti-idiotype antibodies are antibodies that bind to the variable region of another antibody
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What does Rituximab target?
CD20 expressed on B cells including leukemic B cells
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Why is CD20 an ideal target for an antibody?
it is small and has two extracellular loops providing epitope
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what makes the two loops of CD20 a good antibody target
alanine and proline sticking out
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Why would you expose cells with CD20 to CD20 antibodies?
pull them into lipid raft which allows them to use cell signalling molecules present in the raft and sequesters antibodies into platform forming ideal docking station for C1Q molecules for activation of complement?
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What are Raji cells?
Human Leukemic B cells
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What does FcGammaReceptor do?
binds to IgG and is critical for effector function
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what cells express FcR?
effector cells like macrophages and NK cells
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What do FcR's bind too?
Fc regions on antibody
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How do NK cells kill cells?
fcR on surface binds to antibodies bound to cancer cells and cause antibody dependent cellular toxicity
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What are chimeric antibodies?
antibodies with domains from two different species
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Why are chimeric antibodies required?
Immune clearance of antibody from different species
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What is CHOP?
chemotherapy treatment including 4 chemicals
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What is the humanised version of CD20 antibody called?
Ocrelizumab
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What is the fully human antibody of CD20 called?
Ofatamumab
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What is different about Ofatamumab?
Binds to a larger loop of CD20 with higher affinity
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Why would you glyco-engineer a humanised antibody?
to make it more efficient in binding FcR on NK cells
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What has been a problem with rituximab use since its approval in 1997?
Repeated use has lead to resistance mechanism
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How have CD20 antibodies lost their effectiveness?
CD20 lost from membrane due to possible internalisation of the antibody and CD20 complex and subsequent degradation
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What is Trogocytosis?
involves the transfer of plasma membrane fragments from the presenting cell to the lymphocyte
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How has trogocytosis resulted in resistance to rituximab?
Antibody shaving driven by effector cells expressing FcR results in the complex formed between antibody and CD20 being removed resulting in loss of CD20
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How might the tumour environment be adding to resistance to Rituximab?
low expression of FcR due to regulatory or immune suppressive pathway induced by tumour leading to reduced FcR binding and less killing by NK cells
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Why might FcgRIIb be contributing to Rituximab resistance?
FcgRIIb expressed on cancerous B cells binds to Fc of antibodies but elicits an inhibitory signal supressing action of antibody
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Why is combination therapy beneficial when treating B cell lymphoma
Blocking FcgRIIb and treating with rituximab ensures that the action of rituximab is not supressed by inhibitory signals of FcgRIIb
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What are CD27 molecules?
Immune stimulatory molecules and can overcome some inhibition of immune system
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What does stimulation of CD27 on T and NK cells do?
Increases chemokine and IFNg release
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What does released IFNg do?
Leads to myeloid activation and infiltration
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How could an antibody help to kill cancer cells in a tumour supressive environment?
Antibody binding releases inflammatory molecules which enable recruitment of myeloid cells to tumour and activate FcR
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Why is combining anti-CD27 and anti-CD20 a good idea to treat a tumour in a supressive environment?
binding of CD27 causes release of IFNg and chemokines which cause recruitment of myeloid cells and activation of FcR receptors on effector cells and antibody binds CD20 and its Fc region binds the upregulated FcR on effector cells
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how do direct tumour-targeting mAbs kill tumours primarily?
Macrophage-mediated phagocytosis
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How can we enhance efficiency of mAbs against tumours?
Stimulation of CD27 on NK and T cells
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What is Rheumatoid arthritis?
inflammatory autoimmune disease
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what is infliximab primarily used for?
treatment of patients with psoriasis
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What does Infliximab target?
TNF-alpha
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What is osteoarthritis?
Cartilage thinning through mechanical damage has led to destruction of bone
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What distinguishes osteoarthritis and rheumatoid arthritis?
Presence of inflammatory molecules and inflammation in Rheumatoid Arthritis
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What are Rheumatoid factors?
IgM antibodies directed against Fc region of IgG
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Why do Rheumatoid factors induce inflammation?
Form immune complexes that are implicated in complement system and are deposited in joints recruiting immune cells
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Rheumatoid Arthritis is a chronic autoimmune disease characterised by the presence of Rheumatoid factor and ...
Anti-citrullinated protein/peptide autoantibodies
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Why is TNFalpha implicated in Rheumatoid arthritis?
TNFalpha have downstream effects on other cells in the synovial joint and release inflammatory molecules
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What cells can TNFalpha activate?
Downstream monocytes and endothelial cells
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What happens if TNFalpha activates endothelial cells?
They start expressing adhesion molecules leading to recruitment of immune cells and activation of synovial fibroblasts
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What happens if TFNalpha activates monocytes?
They produce IL-1 and activate T cells and synovial fibroblasts
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What does activation of the synovial fibroblasts by TNFalpha result in?
Secretion of IL-8 and matrix metalloproteinases
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How does activation of synovial fibroblasts contribute to inflammation in Rheumatoid Arthritis?
Secretion of Il-8 stimulates migration of T cells and monocytes through endothelium into synovial tissue and releases matrix metalloproteinases which attack cartilage
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What is Etanercept?
a fusion protein of TNFR2 and LTalpha, fused to Fc domain of human antibody
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Why does Etanercept have TNFR2 and LTalpha?
So it can bind to TNF
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What does Infliximab do?
binds to TNFalpha through mouse variable region and effector function from IgG1 human region
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Why/When would inhibiting TNFalpha be beneficial?
in chronic inflammation
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What are the problems of using TNF inhibitors for immunotherapy?
TNF is important in dendritic cell maturation and is important in host defence against organisms that induce granuloma formation
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Name 3 types of organism that TNF inhibition causes increased susceptibility to
Listeria, mycobacteria, fungi
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