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pr3152 > biopharmaceutical products derived from endocrine and immune system i > Flashcards

biopharmaceutical products derived from endocrine and immune system i Flashcards

1
Q

what is the function of the immune system

A

protect body from foreign proteins and invading organisms

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2
Q

what are the cellular and humoral components in innate and adaptive immunity

A

cellular for innate: phagocytes, NK, mast cells, dendritic cells
humoral for innate: cytokines, complement proteins

cellular for adaptive: T and B cells
humoral for adaptive: cytokines, Ab

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3
Q

what is cell mediated response

A

by cytotoxic T cells

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4
Q

what is humoral response

A

Ab produced by plasma cells bind to specific epitopes expressed by pathogen -> Fc domain of Ab bind to Fc receptor expressed by effector cells -> activated effector cells engulf or lyse pathogen -> pathogen clearance

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5
Q

what is the antibody structure

A

2 heavy and 2 light chains, Fab and Fc domain, Vh Vl, Ch Cl in Fab domain

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6
Q

what is the function of Fab domain

A

with Ag specificity for binding to Ag

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7
Q

what is the function of Fc domain

A

to trigger immune response by binding to Fc receptor of effector cells/ complement proteins

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8
Q

what type of post translational modification does Fc domain undergo

A

glycosylation

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9
Q

what does different AA sequence in Vh and Vl chains allow for

A

Ag binding specificity diversity

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10
Q

how many CDRs does each heavy and light Fab arm have

A

3

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11
Q

how many paratopes does an Ab have

A

2

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12
Q

differentiate between epitope and paratope

A

epitope is on Ag, paratope is on Fab region of Ab

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13
Q

how many CDRs does one paratope of an Ab have

A

6 (three from heavy, three from light)

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14
Q

what is antigen affinity

A

measure of strength of interaction betwen Ab and paratope

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15
Q

what is antigen specificity

A

measure of goodness of fit between paratope and epitope

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16
Q

what does antigen specificity indicate

A

indicates the ability of paratope to distinguish similar and dissimilar antigens

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17
Q

what can low antigen specificity result in

A

cross reactivity where paratope interacts with more than one epitope

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18
Q

what is meant by avidity

A

strength with which an Ab binds to its target, measure of total binding strength when there is multiple antigenic sites

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19
Q

where are T cell receptors found

A

on surface of T cells

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20
Q

what are the components of a TCR

A

an alpha and beta chain, each with a variable and constant region and a transmembrane region and short cytoplasmic tail

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21
Q

what are the components of each alpha and beta chain

A

each alpha and beta chain consists of two extracellular domains that is glycosylated with carbohydrates

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22
Q

what is the purpose of transmembrane region

A

to cut across the highly lipophilic plasma membrane

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23
Q

what is the characteristic of the transmembrane region in order to meet its purpose

A

AA sequence composes of hydrophobic/ non polar to form stable interactions with phosphobilipid layer

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24
Q

what is the drawback of the short cytoplasmic tail

A

may be too short for signal transduction for T cell activation upon Ag binding

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25
Q

what does the short cytoplasmic tail of a TCR encourage

A

formation of TCR complex

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26
Q

what is the purpose of the variable and constant region of a TCR

A

variable region is for Ag binding, constant region contains Cys residues to form disulfide bonds between alpha and beta chains

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27
Q

how are TCR complexes formed

A

through CD3 dimers

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28
Q

how many CD3 dimers are required to form a TCR complex

A

3

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29
Q

what are the CD3 dimers required to form a TCR complex

A

CD3epsilon-gamma, CD3epsilon-delta, CD3zeta-zeta

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30
Q

why are extracellular domains of cell surface receptors important

A

it allows ligands to bind and trigger changes within receptors so that intracellular components are able to trigger a series of signal transduction reactions which leads to receptor activation and downstream signalling events

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31
Q

how many ITAMs does a TCR complex have and where are they located

A

each CD3gamma, CD3epsilon, CD3delta have one ITAM
each CD3zeta has three ITAMs
total 10 ITAMs

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32
Q

what occurs to the ITAMs when there is TCR-Ag binding

A

ITAMs get phosphorylated which is a post translational modification which leads to a series of downstream T cell signalling events hence causing T cell activation

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33
Q

where are B cells developed

A

bone marrow

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34
Q

how are B cells and its Ab developed

A

progenitor B cells (original) have heavy and light chain that are able to undergo rearrangement -> rearrangement of IgG -> clones of immature B cells that have B cell antigen receptor -> leaves bone marrow and enter circulation and peripheral lymphoid tissues -> if B cell encounter pathogenic Ag, it will become activated -> produce first line immune response IgM -> gene rearrangement of Fc domain of IgM -> undergo class switching produce IgG instead of IgM -> continuous rearrangement of genes in Fab arms -> produce different hypervariable CDR -> IgG Ab of varying Ag specificity

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35
Q

when is IgM produced

A

exposure to pathogenic Ag

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36
Q

when is IgG produced

A

gene rearrangement and class switching

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37
Q

where are T cells developed

A

bone marrow

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38
Q

where do T cells go too after developing in bone marrow

A

to primary lymphoid tissue (thymus) then to secondary lymphoid tissue (lymph nodes and spleen)

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39
Q

why is there TCR diversity

A

genetic recombination of DNA segments in Valpha and Vbeta regions

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40
Q

how many CDR are there on Valpha region of TCR and how is it created

A

CDR1alpha, CDR2alpha, CDR3alpha
VJ recombination

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41
Q

how many CDR are there on Vbeta region of TCR and how is it created

A

CDR1beta, CDR2beta, CDR3beta
VJ recombination followed by VDJ recombination

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42
Q

how are memory T cells produced

A

during an infection, Ag driven expansion of Ag specific T cells clears off invading Ag, effector T cells die after clearing of Ag, remaining Ag specific T cells differentiate and become memory T cells that will have faster and more potent effect if reexposure to same Ag

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43
Q

where are memory T cells found

A

lymphoid tissues, bone marrow, specific organs

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44
Q

what are MHC molecules

A

molecules that are cell surface proteins required for adaptive immune system to function

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45
Q

what are the two characteristics of MHC molecules

A

polygenic and polymorphic

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46
Q

what is meant by polygenic

A

made up of multiple genes

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47
Q

what is meant by polymorphic

A

each MHC made up of different alleles that can vary by up to 20 AA

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48
Q

what is the benefit of MHC being polygenic

A

being made up of different genes suggests different peptide binding specificities -> present different Ag to T cell -> broader coverage of Ag

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49
Q

what is the benefit of MHC being polymorphic

A

increases diversity of MHC being expressed in each individual -> broader coverage of Ag

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50
Q

what is the function of MHC

A

bind to peptide fragment (Ag fragment) and present to T cell to aid the immune system in differentiating self from nonself/ foreign pathogen

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51
Q

what is the process of MHC binding to Ag fragment and presenting to T cell

A

Ag picked up by APC -> phagocytosis -> forms Ag fragments that get bound to MHC II -> peptide-MHC (pMHC) presents to CD4+ -> activate CD4+ to produce cytokines like IL2 -> activate CD8+ and B cell

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52
Q

what type of immunity does activation of CD8+ lead to

A

cell mediated immunity

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53
Q

what type of immunity does activation of B cell lead to

A

humoral immunity through secretion of Ab

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54
Q

do MHC molecules have immune function

A

no

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55
Q

where are MHC I molecules present in

A

present in all nucleated cells and platelets

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56
Q

are MHC I molecules present in RBC why

A

no as RBC has no nucleus

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57
Q

what is the function of MHC I molecule

A

bind to peptide fragments of endogenous Ag and present to CD8+

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58
Q

what are examples of endogenous Ag

A

normal self Ag, viral components from a virus infected cell, neoantigens produced by cancer cells

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59
Q

where are MHC II molecules present in

A

APC and B cells

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60
Q

what is the function of MHC II molecules

A

bind to peptide fragments of exogenous Ag and present to CD4+

61
Q

what are exogenous Ag

A

usually foreign Ag belonging to invading pathogens

62
Q

what are MHC molecules regulated by

A

IFNalpha and IFNgamma

63
Q

what are IFN

A

cytokines

64
Q

what are cytokines

A

substances secreted by immune cells

65
Q

what happens if levels of IFNs increase

A

expression of MHC I/II molecules increases

66
Q

why is IFNalpha produced

A

as an early response to viral infection

67
Q

what does IFNalpha do

A

increases transcription -> increase expression of MHC molecules -> T cell activation

68
Q

what is IFNalpha useful for

A

enhancement early phase antiviral response

69
Q

why is IFNgamma produced

A

immunomodulatory cytokine

70
Q

what does IFNgamma do

A

increases expression of MHC molecules -> activate T cells

71
Q

what is IFNgamma useful for

A

enhancing immune response

72
Q

what is the function of a proteasome

A

protein complex ubiquitously in cells that degrade unwanted or damaged proteins by proteolysis

73
Q

what is the structure of a proteasome

A

consists of proteases that cleave peptide bonds so that proteins are degraded into peptide fragments of about 15AA through proteolysis

74
Q

where are pMHC I formed

A

in ER/ golgi apparatus

75
Q

how are pMHC I presented to CD8+

A

CD8+ has CD8 receptors which binds to MHC I molecule present in pMHC to bring close proximity of pMHC to its TCR on cell surface -> establish binding between TCR and antigenic peptide -> trigger signalling events involving activated TCR

76
Q

what happens to degraded/ unwanted proteins due to wear and tear from daily cellular activities

A

unwanted -> undergo proteolysis by proteases into peptide fragments -> picked up by MHC I molecules to form pMHC I -> expressed on nucleated cells and platelets -> present to CD8+ -> CD8 receptor dock to MHC I portion -> bring proximity to TCR -> TCR bind to antigenic peptide -> trigger signalling events

77
Q

where are pMHC II formed

A

ER

78
Q

what happens to exogenous Ag

A

exogenous Ag taken into APC in endosomes -> undergo proteolysis by proteases into peptide fragments -> picked up by MHC II molecules to form pMHC II -> expressed on surface of APC -> presented to CD4+ -> CD4 receptors dock to MHC II portion -> bring proximity to TCR -> TCR bind to antigenic peptide -> trigger signalling events

79
Q

what are the classes of cytokines

A

IFN, IL, hematopoietic growth factors, cytokines, tumor necrosis factors

80
Q

what is IFN produced by

A

cells in response to viral infection, tumor, other biological inducers

81
Q

what is IL produced by

A

leukocytes

82
Q

what is TNF produced by

A

usually present in small amounts but increase production by activated macrophages in response to inflamm conditions

83
Q

what are the effects of IFN

A

promote antiviral state in neighbouring cells, regulate immune response

84
Q

what are the effects of IL

A

affect growth and differentiation of hematopoeitic and immune cells, regulate immunity and inflamm and hematopoiesis

85
Q

what are the effects of hematopoietic growth factors

A

stimulate cellular division and differentiation of blood cells from bone marrow precursors

86
Q

what are the effects of chemokines

A

stimulate leukocyte chemotaxis and activation

87
Q

what are the effects of TNF

A

pro inflamm and pro apoptosis actions

88
Q

what is chemotaxis

A

movement of immune cells in response to chemical stimuli

89
Q

what are the physical properties of cytokines

A

small proteins of <20kDa, glycosylated glycoproteins, short half life, secreted out of cells, action short range

90
Q

what is the generic moa of cytokines

A

bind to specific cytokine receptor on surface of effector cell to trigger downstream effects

91
Q

what is the moa of IFN

A

interfere with viral replication

92
Q

what is the moa of IL2

A

immunomodulatory - stimulate growth and differentiation of T cells via autocrine effect, B cells and NK

93
Q

what is the moa of IL11

A

stimulate proliferation of hematopoietic cells and induce megakaryote maturation -> incr PLT formation

94
Q

what is the moa of TNF

A

hematopoietic effect

95
Q

what is the biological effects of IFN

A

induction of cellular resistance to viral attack, regulation of most aspects of immune function, regulation of growth and differentiation

96
Q

what is the biological effects of IL2

A

activation of T cell

97
Q

what is the biological effects of IL11

A

hematopoietic cofactor

98
Q

what is the biological effects of TNF

A

help restore severe deficiency in hematopoeitic cells due to chemotx/ radio tx

99
Q

what are the kinds of IFN and what are their type classification

A

type I - IFN alpha, beta
type II - IFN gamma

100
Q

what type of cytokine is IFNgamma and what does it do

A

immunomodulatory cytokine which activates resting macrophages and monocytes to increase phagocytic activity (immunostimulation)

101
Q

what produces IL2 and IL11

A

T cells produces IL2, fibroblasts and bone marrow stromal cells produces IL11

102
Q

what are the two types of colony stimulating factors

A

(grastim) G-CSF, (gramostim) GM-CSF

103
Q

what are examples of G-CSF

A

pegfilgrastim, lenograstim

104
Q

what are examples of GM-CSF

A

sargramostim

105
Q

what type of glycosylation in G-CSF and GM-CSF

A

O linked in G-CSF, N linked in GM-CSF

106
Q

what is G-CSF useful for

A

it increases neutrophils so good for treating chemotx induced neutropenia

107
Q

what is GM-CSF useful for

A

it increases neutrophils, monocytes, eosinophil counts which is good for accelerating myeloid cell recovery after BMT, antiviral, antifungal therapy, CD

108
Q

what is antiserum

A

animal sera containing polyclonal Ab raised by immunising animal with a particular Ag

109
Q

how is antiserum produced

A

whole blood collected from immunised animal -> left to clot/ add coagulant -> clotting factors removed -> centrifugate to separate cellular components -> serum obtained as supernatant -> raw serum further purified

110
Q

how is raw serum further purified

A

eliminating serum proteins and enriching the fraction of Ig that reacts with target Ag through protein A/G purification or immunoaffinity column chromatography

111
Q

which method of raw serum purification produces more specific Ig

A

immunoaffinity purification method

112
Q

what is the drawback of using antiserum and what is it mainly used for

A

immunogenicity issues and mostly used for passive immunisation

113
Q

what are the advantages of monoclonal Abs and what are its uses

A

highly specific and high homogeneity

highly specific: recombination protein purification
high homogeneity: reproducible for commercial development (target specific therapeutic molecules, test kits, experimental research techniques)

114
Q

what are the types of mAbs

A

murine, chimeric, humanised, recombinant human

115
Q

how are mAbs produced

A

from one B cell

116
Q

how are murine mAbs produced

A

hybridoma technology

117
Q

what are the limitations of murine mAbs

A

induces immunogenicity and fail to trigger a number of effector functions and shorter half lifes (30-40h)

118
Q

what percentage of chimeric mAbs and humanised mAbs are human

A

~75% and 90%

119
Q

how are chimeric mAbs produced

A

replacing AA sequence in Ch and Cl of murine mAbs as not required for binding to Ag, Ag binding Vh and Vl fragments conserved

120
Q

how are humanised mAbs produced

A

only hypervariable CDR regions kept

121
Q

how are recombinant human mAbs produced

A

using DNA technology to genetically engineer such that AA sequence of heavy and light chains fully human

122
Q

what are the suffixes for each type of mAbs

A

murine: -omab-
chimeric: -ximab-
humanised: -zumab-
recombinant: -mumab-

123
Q

what are some applications that do not require Fc domain

A

antagonism of enzyme actions, neutralise receptor ligands like hormones and cytokines to counteract overproduction of cytokines, neutralise toxins

124
Q

what does addition of Fc domain provide

A

increase half life -> decr freq of administration

125
Q

what are the types of Ab derivatives

A

Ig conjugate, F(ab’)2, Fab, ScFv, BiTEs, triomabs

126
Q

how are F(ab’)2 and Fab derived

A

cleaved by proteases pepsin and papain respectively

127
Q

what is the structure of Ig conjugate

A

radioisotope, cytotoxic cytokine or toxin conjugated to full length Ab

128
Q

what is the structure of ScFv

A

AA sequence in Vh and Vl in single polypeptide chain

129
Q

what is the structure of bispecific Tcell engagers

A

two distinct Fab regions

130
Q

what is the structure of triomabs

A

two distinct Fab regions with Fc region

131
Q

where does fucose bind to in naturally occurring IgG

A

Asn297

132
Q

what is the effect of fucosylation

A

reduced affinity to subtype of Fc receptor called FCRgammaIII found on effector cells -> less Ab dependent cellular cytotoxicity induction by effector cells

133
Q

what is the process of TIL

A

tumor removed from patient -> isolate TILs -> primed and expanded ex vivo -> infused back into patient -> therapeutic TIL reinfiltrate tumor -> recognise and bind to Ag -> attack cancer cells

134
Q

what are the limitations of TIL

A

excised tumor mass may have low quantities of TILs

expanded naturally occurring tumor specific T cells are heterogenous with different specificity thus may not be lethal enough

limited or none of expanded T cells have high affinity

135
Q

what is the process of TCR-T and CAR-T

A

T cell isolated from peripheral blood of patient -> expand to ensure sufficient quantity -> genetically modified under lab conditions -> develop tumor Ag specific T cells

136
Q

what makes a TCR Ag specific

A

Valpha, Vbeta in TCR

137
Q

how are the T cells cloned

A

using a retro/lentiviral vector that have high transduction efficiency

138
Q

what does high transduction efficiency mean

A

large amount of T cells will carry the desired gene aka high tumor specificity and less heterogeneity

139
Q

what are the advantages of TCR-T

A

contain full TCR complex -> can infiltrate tumor

contain full TCR complex with the six CDRs (three on each Valpha and Vbeta) -> allow activity even at low Ag densities

slower onset due to lag time required for TCR to bind to pMHC bc bulkier, but longer duration and extended killing

140
Q

what are the limitations of TCR-T

A

since MHC are polymorphic and polygenic, TCR can only recognise and work for patient subpopulation that have same allele

less safe than TIL due to
1. on target off tumor - target normal cell expressing same Ag
2. off target - TCR-T cells not specific and cross react with other antigenic fragments
3. cytokine release syndrome

141
Q

what is the difference between CAR-T and TCR-T

A

CAR-T utilises a ScFv as sole extracellular domain so instead of cloning full TCR onto retro/lentiviral vector, clone Vh and Vl of identified Ab onto the vector

142
Q

what are the advantages of CAR-T

A

recognise and bind to unprocessed tumor Ag without MHC processing but depends on ScFv specificity and its likelihood of binding to lookalikeness

143
Q

what are the limitations of CAR-T

A

only bind to cell surface Ag, ineffective against solid tumors

ScFv may drive CAR-T cells into an Ag independent mechanism

only activated at higher Ag densities and strength of interaction depends on ScFv

faster but weaker killing due to the fact that only one subunit aka ScFv that binds to Ag which leads to weaker CAR signalling and activation

on target off tumor due to B cell aplasia (attacking normal B cell expressing the same target)

even more CRS

144
Q

compare the difference in structure of gen 1-4 CAR-T and its benefits/ limitaitons

A

gen 1: ScFv with CD3zeta - still very short cytoplasmic tail, insuff for signalling

gen 2: ScFv with CD3zeta and CD28/4-1BB - second activation allows for stronger signalling

gen 3: ScFv with CD3zeta and CD28 and 4-1BB

gen 4: ScFv with CD3zeta and CD28 and 4-1BB with transgene - transgene activation expresses cytokine like IL12 which exert autocrine and/or paracrine effect on T cells at target site and activate more T cells to eliminate cancer cells

145
Q

where are checkpoint molecules found

A

expressed on T cell surface

146
Q

what happens if ligands bind to checkpoint molecules

A

suppresses T cell activity

147
Q

what are examples of checkpoint molecules expressed on T cells

A

cytotoxic t lymphocyte associated protein (CTLA-4) and programmed death 1 (PD-1)

148
Q

what does CTLA-4 compete with and bind to

A

compete with CD28 also expressed on T cell for binding to costimulatory CD80/CD86 on APC

149
Q

what are the types of cancer vaccines

A

cell (tumor cell/ dendritic cell)
protein/ peptide
nucleic (DNA/ RNA)

pr3152 (6 decks)

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