Biontech brings antibody production into the body

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," nclick="getInfo('15080'); return false;">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, nclick="getInfo('15080'); return false;">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 tumours.

Other groups are looking at claudin-18.2, including nclick="storyWordlink('Astellas'); return false;">Astellas, which has a phase II monoclonal antibody, nclick="storyWordlink('IMAB362'); return false;">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, nclick="storyWordlink('Astellas'); return false;">Astellas is active here, with nclick="storyWordlink('IMAB027'); return false;">IMAB027 in phase II development for ovarian cancer.

Bispecific

But rather than using its mRNA technology to induce patients to produce a MAb, nclick="getInfo('15080'); return false;">Biontechsought to produce bispecific antibodies. In the mouse study these were directed against CD3, a protein present on effector T cells, plus one of three tumour-associated antigens: claudin-6, claudin-18.2 or nclick="storyWordlink('EpCAM'); return false;">EpCAM.

The idea behind this nclick="storyWordlink('"bispecific antibody"'); return false;">bispecific antibody approach – also employed by nclick="getInfo('1006'); return false;">Amgen’s nclick="storyWordlink('Blincyto'); return false;">Blincyto, though this is manufactured in the traditional manner – is to bring T cells into contact with tumour cells, triggering tumour cell destruction.

The early signs suggest that nclick="getInfo('15080'); return false;">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 tumour," Mr Marett says.

In the study, mRNA encoding the bispecific antibodies was delivered intravenously in a nanoparticle lipid formulation. According to Mr Marett, nclick="getInfo('15080'); return false;">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 nclick="getInfo('15080'); return false;">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 nclick="getInfo('15080'); return false;">Biontech nclick="storyWordlink('"cancer vaccine"'); return false;">cancer vaccine could be delivered to dendritic cells in vivo. 

Longer lasting

As well as potentially being quicker and cheaper to produce than antibodies manufactured outside the body, nclick="getInfo('15080'); return false;">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 nclick="getInfo('15080'); return false;">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." nclick="getInfo('15080'); return false;">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.

Modified mRNA

In the mouse study, nclick="getInfo('15080'); return false;">Biontech used modified mRNA so as not to trigger an immune response – making it different to the company’s nclick="storyWordlink('"cancer vaccine"'); return false;">cancer vaccine approach, which uses natural mRNA that has been "adjusted that to make it more stable and nclick="storyWordlink('better'); return false;">better at translation", Mr Marett explains.

nclick="getInfo('15080'); return false;">Biontech is developing personalised mRNA vaccines in partnership with nclick="getInfo('1057'); return false;">Roche’s nclick="getInfo('1030'); return false;">Genentechsubsidiary, 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 nclick="getInfo('15080'); return false;">Biontech fall foul of nclick="storyWordlink('Moderna'); return false;">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."