Biologics & drug development Flashcards by X X

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

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3 types of biological drugs examples

mabs,
proteins/peptides eg growth factors
RNA based therapeutics. microRNAs

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list some classes of biologic drugs on market (pie chart)

mabs: majority
synthetic immunomodulators
vaccines
recombinant hormones

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type of molecule that is developed to target mRNA for degradation?
(rel new class of biologic.)

RNAi based theraps:

antisense RNA molecules

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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

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why do small molecule drugs such as celecoxib sometimes end in ib?

= inhibitor small molecule drug

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lead identification (LI) is done through what process?

high throughput screen

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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

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primary screen is done using what process?

enzyme cell free assay

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cell assays are done as part of primary or secondary screens?

secondary

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3 things studied during in vivo studies?

function, moa and tox

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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 :(

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the 4 stages in antibody drug pipeline?

antigen prep
lead antibody discovery
lead optimisation
manufacturability assessment

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how is the manufacture different between small molecules and large mols (biologics)?

small: chemicals synthesis
biologics: cell culture

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bioanalytical assays for PK assessment for small mols are … and ….
eg

simple + specific
eg LC-MS/MS

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bioanalytical assays for PK assessment for biologics are … and require …..
eg

complex + require biologic agents
eg ELISA

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biologics: quicker to develop initially compared to small mols, but….

more effort to put in later to maintain, monitor px

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small molecule drugs can get through cell membranes and get into cells easily to target what?

intracellular molecules

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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

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why are antibody drugs generally restricted to targeting transmembrane receptors such as TNFa or ligands?

too large to penetrate cells

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lapantinib binds to what to inhibit the HER2 receptor to reduce breast cancer cell growth?

intracellular phosphorylation domain

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where does the mab trastuzumab bind to target HER2 receptors to reduce breast cancer cell growth?

her2 receptor on cell membrane

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give 2 inhibitors of HER2+ breast cancer cells

lapatinib (kinase inhibitor)
trastuzumab (mab)

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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

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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

Biologics & drug development Flashcards

(61 cards)