Biologics & drug development Flashcards
LO
- to know the different types of biological drugs and the differences to small molecules
- to know when an antibody approach is suitable for developing a therapeutic
- to know how to deliver antibody based drugs are being adapted to deliver new modes of action and improve efficacy
3 types of biological drugs examples
mabs,
proteins/peptides eg growth factors
RNA based therapeutics. microRNAs
list some classes of biologic drugs on market (pie chart)
mabs: majority
synthetic immunomodulators
vaccines
recombinant hormones
type of molecule that is developed to target mRNA for degradation?
(rel new class of biologic.)
RNAi based theraps:
antisense RNA molecules
how do antisense RNA mols target mRNAs for degradation + silence particular genes? ?? + use?
by admin. ANTIsense oligonucleotide that can be degraded to specifically target particular mRNAs for degradn
often sued for if have dysfunctional gene/ pathway: design oligonucleotide to silence it
why do small molecule drugs such as celecoxib sometimes end in ib?
= inhibitor small molecule drug
lead identification (LI) is done through what process?
high throughput screen
problems/ limitations with target identification process?
10,000 mols screened, only 1 approved drug maybe, after yeras and £billions
90% of drugs in development fail
primary screen is done using what process?
enzyme cell free assay
cell assays are done as part of primary or secondary screens?
secondary
3 things studied during in vivo studies?
function, moa and tox
how does antibody drug pipeline compare to the screening cascade w small molecule drugs (target identification, validation etc)?
rapid development time (few yrs)
4 steps
target -> synthetic antibody for target = drug :)
BUT have PK, PD complications :(
the 4 stages in antibody drug pipeline?
antigen prep
lead antibody discovery
lead optimisation
manufacturability assessment
how is the manufacture different between small molecules and large mols (biologics)?
small: chemicals synthesis
biologics: cell culture
bioanalytical assays for PK assessment for small mols are … and ….
eg
simple + specific
eg LC-MS/MS
bioanalytical assays for PK assessment for biologics are … and require …..
eg
complex + require biologic agents
eg ELISA
biologics: quicker to develop initially compared to small mols, but….
more effort to put in later to maintain, monitor px
small molecule drugs can get through cell membranes and get into cells easily to target what?
intracellular molecules
what sort of mols do small molecules target inside cells?/ their effect
intracellular mols…
kinases (enz)
inhibit phosphatases
or bind intarcellular signalling downstream of receptors
why are antibody drugs generally restricted to targeting transmembrane receptors such as TNFa or ligands?
too large to penetrate cells
lapantinib binds to what to inhibit the HER2 receptor to reduce breast cancer cell growth?
intracellular phosphorylation domain
where does the mab trastuzumab bind to target HER2 receptors to reduce breast cancer cell growth?
her2 receptor on cell membrane
give 2 inhibitors of HER2+ breast cancer cells
lapatinib (kinase inhibitor)
trastuzumab (mab)
what molecule can be developed when you want to target 2 differerent proteins or for 2 sites on the same proteins (bi paratopic)?
bi-specifics
how is a bi-specific antibody made? by …
joining 2 halves of different antibodies
and inhibits 2 actions. dual functionality
how do antibody drug conjugates work (ADC)? to deliver drug to target cell eg cytotoxic compounds, chemos
delivery of payload -> target cells,
antibody targets specific antigen,
drug linked to antibody + delivered -> target cell
why may you consider antibody drug conjugates for delivery of chemotherapeutic agent?
as want it to be selective to only cancer cells.
ADC allows _____ delivery and stops …..
selective.
systemic/ generic activity of toxic drugs
how can tissue penetration of antibody drugs be improved?
use small part of antibody: Fabs and scFvs instead
… more Fabs bound together: inc specificity
why does tissue penetration of antibody drugs need to be improved?
large, so dont enter cells easily
antibody oligonucleotide conjugates such as oliogonucleotide antisense allow silencing of?
intracellular drug targets
delivery across plasma membrane is not a challenge for antibody oligonucleotide conjugates, true or false?
false
antibodies used to target specific cell surface receptor and are conjugated to oligonucleotide via what?
linker
why are most biologics given iv, sc or im?
oral BA poor due to enzymatic digestion in GIT
why do biologics take longer to get to peak conc?
absorbed slowly due to large size
is biologic distribution better or poorer compared to small molecules?
poorer
biologics are eliminated mainly via intracellular lyosomal proteolytic degradation, binding to X allows for recycling of antibodies back into circ?
FCRn receptors
true or false, biologics are prone to multiple interactions that impact on the pk and treatment response?
true
what interaction that biologics are prone to may impact on PK + treatment response?
- exposure to factors in blood eg platelets
- binding to neonatal Fc receptors (FcRn)
- immunogenecity eg prodn of ADA + neutralising antibodies
- interactions w other drugs (polypharmacy)
whats the critical requirement for biologic development in preclinical models during drug discovery/ development stages?
extensive PK/PD studies!
what is romiplostim (Nplate 250)?
thrombopoietic mimetic (a fusion protein analog of it) for px w ITP (immune thrombocytopenia)
how does romiplostim promote platelet production
bind to thrombopoietin receptor
what is thrombopoeitin?
hormone that regulates platelet production
binding of romiplostim to platelets affects ….
its clearance
why is monitoring required for romiplostim?
high conc of drug in serum in px w low platelet count,
as count is boosted low conc of drug in serum as it becomes less effective
… as drug starts working, platelets inc = affects availabilty of drug
production of 2 things that can cause immunogenicity to biologics?
production of anti drug antibodies (-> AEs)
neutralising antibodies (NAb)
effect of production of neutralising antibodies (NAb) on biologics? cause immunogenicity
decrease in efficacy over time + potential treatment failure
what is the moa of infliximab?
binds to TNFa and prevents TNFa binding to TNF receptor of target cells
infliximab: mab drug used in what conditions 3…
and why?
RA, Crohn’s, Psoriasis
as all have inc TNFa
drug designed to mop up excess TNFa + prevent it from binding to TNF receptor
infliximab is chimeric mab that binds to TNFa, what does this mean and why can it lead to immunogencity?
variable domans from mouse combined w constant domains from human to reduce immunogencity but still risk of immune response
why might you see reduced conc of infliximab in serum after 6 months on treatment?
production of ADA in response
immunogenecity
px taking infliximab, serum drug levels used to monitor what 2 things to check effectiveness of drug?
hm drug gone into circ
hm ADA developing
=== how effective drug is
ADAs produced by body in response to being given (infliximab) drug. why dont you want these in circn? 2
AEs + could neutralise infliximab effectiveness
why is there a lower risk of an immune response in patients that use adalimumab compared to some of the other mabs in its drug class?
full human antibody (no mouse)
(BUT still get some ADAs developing)
what type of drug: adalimumab
TNFa mAb
immunogenecity w adalimumab treatment. still get development and increase of what, w time?
ADAs.
PK assessments can predict what?
treatment failure
2 different management strategies for immunogencity that do not involve another drug for managing it?
switch treatment or treatment breaks
why is methotrexate a good option to manage immunogenicity?
attentuated ADA production to TNFa mAbs
(diff MOA than TNFa antibody)
what effect do inflammatory cytokines produced from conditions like RA have on simvastatin serum levels?
px w RA + other inflammatory conditions have elevated pro inflammatory cytokines, reduces CYP activity, reduces metabolism in liver + increases simvastatin exposure
outline the DDI between tocilzumab and simvastatin?
causes increase CYP activity in liver as inflammation reduced, reduced simvastatin exposure
