Registration for a live webinar on 'Rare disease clinical trials: challenges and best practices' is now open.
See webinar detailsWe noted you are experiencing viewing problems
-
Check with your IT department that JWPlatform, JWPlayer and Amazon AWS & CloudFront are not being blocked by your network. The relevant domains are *.jwplatform.com, *.jwpsrv.com, *.jwpcdn.com, jwpltx.com, jwpsrv.a.ssl.fastly.net, *.amazonaws.com and *.cloudfront.net. The relevant ports are 80 and 443.
-
Check the following talk links to see which ones work correctly:
Auto Mode
HTTP Progressive Download Send us your results from the above test links at access@hstalks.com and we will contact you with further advice on troubleshooting your viewing problems. -
No luck yet? More tips for troubleshooting viewing issues
-
Contact HST Support access@hstalks.com
-
Please review our troubleshooting guide for tips and advice on resolving your viewing problems.
-
For additional help, please don't hesitate to contact HST support access@hstalks.com
We hope you have enjoyed this limited-length demo
This is a limited length demo talk; you may
login or
review methods of
obtaining more access.
Printable Handouts
Navigable Slide Index
- Introduction
- Complement: a key component in immunity
- Physiological roles of complement
- Complement cascade
- Complement activation
- Distinguishing self from non-self
- Amplification & control
- The engine of the complement system
- Crosstalk with other arms of immunity
- The balance between activation and control
- Many other diseases involve complement
- A single amino acid change creates imbalance
- Age-related macular degeneration (genetic links)
- AMD-associated SNP (polymorphisms)
- Complement therapeutics: historical challenges
- Why can we target complement now?
- Key roles in immunity: where should we inhibit?
- Targets for inhibition in the complement pathway
- Risk of infection and complement
- Risk of Lupus?
- Complement levels
- Prescribing information for Soliris (eculizumab)
- Some current strategies in the clinic
- Clinical validation; Alexion anti-C5 antibody
- Clinical validation; Roche anti-factor D
- Mahalo study; Roche
- Phase III key points
- Phase III studies underway
- Complement inhibition is challenging
- Secondary clinical issues
- Eculizumab prevents intravascular haemolysis
- Strategies for complement modulation
- Antibody engineering to enable systemic dosing
- Demonstration of ‘sweeping’ action
- Localised control: circumvents some issues
- What are homing agents?
- Homing of CR2-DAF to kidney in MRL/lpr mice
- Concluding remarks
- The drug development landscape 2017
- Thank you
- Some useful references
- Disclosures
Topics Covered
- Physiological roles of complement
- Complement activation and control
- Complement-mediated disease
- The challenges of complement drug discovery
- Current drugs in the clinic, highlights and drawbacks
- Strategies for complement inhibition
- The current anti-complement drug development landscape
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Harris, C. (2017, December 31). Complement as a therapeutic target [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 16, 2024, from https://doi.org/10.69645/LEXG6828.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Claire Harris has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Transcript
Please wait while the transcript is being prepared...
0:00
Hello, my name is Claire Harris and I'm a professor at Newcastle University in the UK.
Today, I'll be talking about "Complements as a Therapeutic Target".
0:09
I'll start with an introduction to complements.
It is best known for its role in innate immunity.
That is the first line of defense against the invading pathogen.
However, recent years also demonstrate emerging and critical roles in adaptive immunity,
and I'll mention those in brief here.
So the complement system comprises around 30 proteins,
both activated and controlled,
and these exist alone or in specific complexes.
The majority are made by the liver as well as by cells and tissues.
Although a few proteins such as C7 and properdin are made only at extrahepatic sites.
Complement proteins make up to five percent of total protein and plasma.
That's an enormous amount,
when considering complements as a therapeutic target.
Drugs which target cytokine for
example bind targets with a concentration of just picograms per ml.
Complement is always active through a mechanism known as ticks-over.
The central component C3 activates a very low level in plasma,
and this triggers the alternative pathway of activation.
In health, this is rapidly and effectively controlled,
but it does provide the body with a means to react rapidly in the face of infection.
There is no need to wait for a period of priming.
The complement system is a cascade.
Protein circulates in an inactive form in plasma.
But once the system is activated,
one active protein or protein complex,
activates the next in the pathway.
The system is also amplifying.
One active complex activates more than one protein on the cascade.
An active C3 cleaving enzyme for example,
can rapidly cleave hundreds of molecules of C3.
As each protein is activated,
in many cases, they change shape.
This is true for the proteins generating
the cleaving enzyme that's C3 and factor B, for example,
and also for the proteins generating a lytic pore also
known as a membrane attacker complex or MAC.
The cascade activates very rapidly and efficiently when there is
an activating surface such as a bacterium or an antibody coated surface,
and it can do a lot of damage unless it's properly controlled.
Of course, this is fine if the surface is
foreign. But if the activating surfaces are our own cells,
this can cause a lot of damage and potentially, disease.
This might be the case if an individual lacks
the right complement control proteins for example.
For this reason, there are as many proteins in our body which
control the system as there are which activate it.