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Printable Handouts
Navigable Slide Index
- Introduction
- Introduction to antibody-drug conjugates (ADCs)
- Concept of ADC
- Concept of ADC - the molecular level
- Key design components of an ADC
- How are payloads released?
- Mylotarg and Besponsa
- Kadcyla
- Adcetris
- Outline: design components
- Payload selection criteria
- Payload toxicity vs. potency
- ADC toxicity and “off target” exposure
- ADC payloads lost over time in circulation
- Premature linker cleavage and toxicity
- Stable ADCs
- What causes loss of payload in circulation?
- Direct deconjugation
- Preventing deconjugation
- Site-specific conjugation
- Site-specific conjugation: attaching a payload
- Which sites results in the best conjugates?
- Optimal attachment site
- Linker, conjugation site, & conjugation technology
- Do we need high potency payloads?
- DAR - exposure and efficacy
- PK exposure correlated with hydrophobicity
- Polar functional groups & ADC hydrophobicity
- Effects of reducing hydrophobicity
- DS-8201: A DAR8 ADC showing clinical promise
- Poly-acetal polymeric linkers
- Targeted nanoparticles and liposomes
- ADC toxicity and nonspecific uptake
- Increasing ADC uptake efficiency
- Possible pathways for non-specific uptake
- MEDI4276
- Exposure vs. tumor penetration
- Outline: future prespectives
- Changes in ADC design
- Growing interest in non-oncology ADCs
- Thank you
Topics Covered
- How antibody-drug conjugates work
- How payloads are selected
- Methods for minimizing toxicity and improving potency
- Examples of drugs in clinical trials/market
Links
Series:
Categories:
Talk Citation
Tumey, L.N. (2018, September 26). Current challenges in the design of antibody-drug conjugates [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 11, 2024, from https://doi.org/10.69645/JUPL6725.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. L. Nathan Tumey, Consulting Fees (e.g., advisory boards), Honoraria: Takeda, Cue Biopharma Grant/Research Support (Principal Investigator): Binghamton University Ownership Interest (stocks, stock options, or other ownership interest excluding diversified mutual funds): Pfizer
Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms
Transcript
Please wait while the transcript is being prepared...
0:00
My name is Nathan Tumey and I'm going to be discussing with you this morning a little bit
about some design challenges in the field of antibody-drug conjugates.
Just before we get going with that discussion let me just introduce myself.
I am a professor at Binghamton University in the
School of Pharmacy and Pharmaceutical Sciences; I teach medicinal chemistry here.
I've been here for about a year but prior to joining the faculty here at Binghamton,
I spent the last 15 years in the pharmaceutical industry, most recently
at Pfizer where I spent
about seven years in the field of developing antibody-drug conjugate.
So, my background is in chemistry,
my PhD is in organic chemistry and so I'm going to be sharing with you
my design perspective from the perspective of an organic chemist or a medicinal chemist.
So, realize that as we discuss antibody-drug conjugates,
it is a very broad field and I have
my own expertise and interests in it and I will share with you some
of the highlights of the way the field has been
developing over the last few years from the perspective of a medicinal chemist.
1:05
I'm going to introduce to you some ADC technology,
in general, just to get everybody up to the same speed and then we will
dig into four components of the design
of ADCs and in particular, discussing aspects of payload design,
linker design, conjugation chemistry as well
as factors to consider in the design of the antibody itself.
Then, we'll look at our crystal ball and see where the field is going,
what are some ways that the field is now
different than it was just a few years ago and where it's headed.
1:36
When I discuss ADCs with people the way I like to begin is with
this little picture and this is based on something Amazon presented a few years ago,
an idea or concept for delivering packages around major cities in the US using drones.
At a molecular level that's really
exactly what we're doing with an antibody-drug conjugate.
So, we have a delivery vehicle, which in our case is the antibody, which is kind of
an autonomous drone in many senses just
circulating through the body looking for a target of interest.
When it arrives at that target of interest,
it releases a payload and the payload is really what carries
the biological punch for this drug moiety or for the entity that we're trying to deliver.
So, the payload is what's going to be carrying out the interesting biology; whereas,
the delivery vehicle is simply delivering the payload to the right address.