mRNA’s Next Frontier

The rate of innovation in biotech right now is stunning.

And there’s something on the horizon that could change the very concept of what it means to take a drug.

On October 2, Novartis (NVS) agreed to pay Abogen Biosciences, a private company in Suzhou, China, $575 million up front for an exclusive worldwide license to ABO2203. It also took options on Abogen’s other programs. If Novartis exercises every option and every milestone is hit, Abogen can collect up to about $7.2 billion more, plus royalties.

This could turn into a major investment for Novartis. So what did Novartis buy?

ABO2203 is a strand of messenger RNA (“mRNA”) – which is the same kind of molecule in the COVID vaccines. Except, in this application, it is wrapped in a tiny bubble of fat. Once injected, it winds up in the patient’s liver. And when it gets there, something incredible happens: it teaches the liver cells how to build a sophisticated medicine, a T-cell engager.

Let me explain this in plain English.

As you probably know, your immune system has two main parts. The first are “killer” T cells. They patrol the body, and when they find a cell flying the wrong flag, they kill it. B cells are the arms factories. They make antibodies, the guided missiles that tag invaders for destruction.

In autoimmune disease, some B cells make antibodies that tag healthy tissue. In lupus those missiles tag the kidneys, skin, and joints. In immune thrombocytopenia (“ITP”) they hit platelets, the cells that stop bleeding. In multiple sclerosis, B cells drive the attack on healthy nerves.

Medicine currently has two ways to deal with rogue B cells. The first is to suppress them, every month, for life. That is what the anti-CD20 antibodies do: Roche Holding AG’s (ROG) Ocrevus, Novartis’s own Kesimpta, and TG Therapeutics’ (TGTX) Briumvi. CD20 is a protein on the surface of most B cells, and these antibodies tag those cells for removal. But... those B cells grow back, so the patient must continue to take these drugs. In 2025, those three drugs alone sold about $13.6 billion.

The second way is to reset all the B cells. To do that, doctors must kill every B cell in the body, including the ones hiding in lymph nodes and bone marrow, and let fresh, healthy B cells grow back. The new B cells have not yet learned to attack the patient. In the best cases the disease does not return, and the patient takes no further drugs at all. This isn’t a treatment – it’s a cure.

In 2022, medical researchers Georg Schett and Andreas Mackensen, at University Hospital Erlangen in Germany, gave five patients with severe lupus a single infusion of CD19 CAR-T cells (T cells engineered outside the body to hunt B cells). All five went into drug-free remission, reports Nature Medicine. By February 2024, the Erlangen series reached 15 patients with lupus, myositis, or systemic sclerosis, all in remission or major improvement at a median 15 months, according to the New England Journal of Medicine.

The mechanism to reset all a patient’s B cells is a therapeutic protein called a T-cell engager.

It is a single protein with two grips. One grip (anti-CD3) holds the T cell’s trigger. The other (anti-CD19) holds a protein found on nearly every B cell. Bolted together, the T cell kills the B cell it is tethered to, then moves on to the next one.

While that might sound like science fiction, these technologies have been around for decades.

In 1985, Uwe Staerz and Michael Bevan reported in the science journal Nature that a hybrid antibody could aim T cells at a chosen target. In 1994, Peter Kufer’s group in Munich invented the bispecific T-cell engager format, called BiTE. In 2012, Amgen (AMGN) bought Micromet, the company behind it, for $1.16 billion. The Food And Drug Administration (“FDA”) approved the first BiTE, Blincyto, a CD19 x CD3 engager for leukemia, on December 3, 2014.

In the last three years, seven large drug companies made eight deals to buy or license B-cell reset technologies:

But T-cell engagers have two problems. First, they clear from the blood in hours, so patients have needed continuous intravenous drips. And the even bigger problem is that a large dose can flood the body with inflammatory signals, causing a dangerous reaction called cytokine release syndrome.

ABO2203 attacks both problems by changing who does the manufacturing.

Instead of infusing a finished protein made in a steel tank, the doctor injects a few micrograms of mRNA under the skin. The patient’s cells read the instructions and produce T-cell engagers gradually over several days. Abogen reports its mRNA engager persists in the body for seven to 11 days.

The evidence, so far, is only 12 patients. Abogen Biosciences co-authored a peer-reviewed paper in the journal Cell on September 18 describing three patients with immune thrombocytopenia, and it presented nine lymphoma patients at the AACR cancer meeting in April.

So this is a very new application of mRNA, but it demonstrates an entirely new modality of medicine – teaching the body to create the therapeutic proteins it needs to stop immune system disorders.

I suspect that we will see a wave of innovations as researchers begin to apply this new technology in a wide range of indications. Porter & Co. Biotechnology’s two largest positions, Eli Lilly (LLY) and Novartis (NVS), now have leading platforms in this new modality.

We’ll be watching to see the outcomes of the upcoming Phase II clinical trials with mRNA therapeutic proteins.

Tell me what you think of today’s Daily Journal: porterstansberrydirect@gmail.com

Good investing,

F. Porter Stansberry
Stevenson, Maryland