The New Frontier in Complement Medicines
Lukas Scheibler, Chief Research Officer, Apellis
Innate immunity is a significant potential source of life-changing therapies, according to Apellis, which is using the complement system to develop medicines for a range of complex diseases.
Apellis chief research officer Lukas Scheibler explained how innate immunity and the complement system in particular can yield new ways of treating disease during his presentation at the TIDES USA oligonucleotides and peptides conference.
“We know today that complement is associated in more than 400 human diseases in humans,” Scheibler said. “It’s not the primary culprit in the disease, but it is clear that the complement system is elevated and place some sort of role.”
And hence the complement system provides drug developers with many potential targets across a range of therapeutic areas, according to Scheibler.
“We’re heavily focused on ophthalmology where we look into geographic atrophy and age-related macular degeneration. But the complement system is also believed to play a key role in other blinding diseases such as glaucoma.
“In nephrology, the complement system is actually really involved,” Scheibler said, highlighting the kidney disease C3G as an example. He added that blood diseases and neurology are other areas where complement-targeting drugs can make a difference.
Science
The complement system was first described in the 19th century by researchers Jules Bordet and Paul Ehrlich who noticed that human blood serum contains components that destroy “foreign” cells.
Since then, scientific understanding of the processes involved has advanced significantly, according to Scheibler.
“Today we know that the complement system can be activated by three distinctive pathways: the classical, the lectin, and the alternative pathway,” he said.
“And all of these pathways culminate in the hydrolysis of the protein C3 into C3a and C3b. C3b then can assemble a convertase in an additional enzyme that then cleaves the protein C5 into C5a and C5b. And C5a then forms what is called the membrane attack complex, which leads to the cell death and lysis of foreign cells,” he said.
Complement cascade
In fact, there are around 80 proteins involved in the complement system, which gives drug developers many potential therapeutic targets to choose from.
But some proteins are harder to target than others, according to Scheibler, who cited C3 – the only protein in the cascade that addresses all three activation pathways – as an example of a challenging target.
“The concentration [of C3] in our blood is about 1 milligram per ml [milliliter]. So if you have about 5 liters of blood, there is about 5 grams of C3 floating around in our bodies,” Scheibler said.
“So it doesn’t really matter how potent your peptide, your protein, your inhibitor is, you still have 5 grams you need to block somehow. You would need a massive amount of inhibitor, and therefore a lot of pharmaceutical companies haven’t really dared to go after it.”
Apellis is among the few companies that has targeted C3 by developing an inhibitor called pegcetacoplan. – The inhibitor is present in the company’s FDA-approved products, Syfovre used to treat geographic atrophy, and Empaveli, used to treat blood disease paroxysmal nocturnal hemoglobinuria.
Pegcetacoplan is an analogue of compstatin. It functions by binding C3 inhibiting proteolytic cleavage by C3 convertase, thereby bringing the complement cascade to an abrupt halt.
And because it targets C3, Scheibler said pegcetacoplan has potential use in a wide range of other diseases, adding that the firm is testing Empaveli as a treatment for ALS and transplantation-associated thrombotic microangiopathy.
Formulation
The key to overcoming the challenges that deterred other drug companies from developing C3-targeting drugs lies in the formulation, according to Scheibler.“Of course, a 13 amino acid cyclic peptide that’s purely water soluble has some challenges. First of all, the half-life is going to be enormously short. And second, the solubility is relatively low, he said.
“So we attached a 40-kilovolt linear peg chain on either end of our APL one molecule with a short two amino acid linker. That led to a drastic improvement of the solubility driven by the peg and driven by the massive molecular size, an increase in half-life.”
