Antibodies have transformed the treatment landscape in many diseases, but are time-consuming and expensive to make. "Producing them is a complete pain in the butt," Biontech's chief operating officer, Sean Marett, tells EP Vantage.
The German company believes it has got around the manufacturing issues by developing an mRNA product that stimulates the liver to make its own therapeutic antibodies. It has so far only proven the approach in mice - in a study published today in Nature Medicine - but if it works in humans it could rival traditional production methods, Mr. Marett believes.
Of course, Biontech still has a long way to go and will now need to take its so-called RiboMABs into the clinic. It is "too early to say" what target or targets the group will evaluate in its first human trials, but Mr. Marett highlights claudin-18.2, which featured in the mouse study, as a "promising target". The protein is frequently overexpressed in gastrointestinal and pancreatic tumors.
Other groups are looking at claudin-18.2, including Astellas (ALPMS) (OTCPK:ALPMY), which has a phase II monoclonal antibody, IMAB362, obtained through last year's purchase of Ganymed. "That gives us some confidence in that this is perceived as a good commercial target," Mr. Marett says.
Claudin-6, also used in the mouse study, is another "highly relevant" target, he adds. Again, Astellas is active here, with IMAB027 in phase II development for ovarian cancer.
But rather than using its mRNA technology to induce patients to produce a MAb, Biontech sought to produce bispecific antibodies. In the mouse study these were directed against CD3, a protein present on effector T cells, plus one of three tumor-associated antigens: claudin-6, claudin-18.2 or EpCAM.
The idea behind this bispecific antibody approach - also employed by Amgen's (NASDAQ:AMGN) Blincyto, though this is manufactured in the traditional manner - is to bring T cells into contact with tumor cells, triggering tumor cell destruction.
The early signs suggest that Biontech's project works, at least in mice. "We've demonstrated not only that we get what we expect, bispecific antibodies, but also that they had a therapeutic effect on the tumor," Mr. Marett says.
In the study, mRNA encoding the bispecific antibodies was delivered intravenously in a nanoparticle lipid formulation. According to Mr. Marett, Biontech can tweak these nanoparticles by size and charge to make them home in on different organs; in the mouse trial they were directed to the liver.
Getting mRNA into a cell has long been a problem for the field, but Biontech thinks it has cracked it. "The delivery of mRNA has always been something people have talked about - we've now demonstrated twice that we can deliver sufficient quantities of mRNA to produce antibodies." Another study published in Nature last year showed that a Biontech cancer vaccine could be delivered to dendritic cells in vivo.
As well as potentially being quicker and cheaper to produce than antibodies manufactured outside the body, Biontech's approach could lead to improved pharmacokinetics, the company believes.
Antibodies are cleared from the body in around two hours according to Christiane Stadler, head of Biontech's bispecific unit and lead author of the Nature Medicine paper. "This is why patients have to go around with infusion bags, which is very inconvenient." Biontech's approach leads to sustained production by the liver and a "long-lasting" effect of up to a week, she says, adding that even less frequent dosing could be possible with modifications to the liposomal formulation.
As for potential safety issues, Mr. Marett says that so far there have been no signs of liver toxicity, and no systemic release of pro-inflammatory cytokines. With such a new technology, this is something that will be closely watched in clinical trials.
In the mouse study, Biontech used modified mRNA so as not to trigger an immune response - making it different to the company's cancer vaccine approach, which uses natural mRNA that has been "adjusted that to make it more stable and better at translation", Mr. Marett explains.
Biontech is developing personalized mRNA vaccines in partnership with Roche's (OTCQX:RHHBY) Genentech subsidiary, and has phase I trials ongoing in melanoma and triple-negative breast cancer (Biontech deal sees Roche bet on mRNA, September 21, 2016).
In the new RiboMAB application, might Biontech fall foul of Moderna, which has claimed it holds the patents for any mRNA modification? Mr. Marett doesn't think so. "That's not true. No one has all of the IP related to modified mRNA currently."
He concludes: "This gives you a very rapid platform to produce diverse antibodies in the body." Now Biontech just has to prove it works in humans.
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