Human Lymph node (PD1, CD3, CD8, KI67)
Courtesy Corinne Thomas & Souâd Naimi–Molecular Histopathology & BioImaging, Sanofi

The immune system is the body’s most loyal defender, thwarting pathogens and other hazardous invaders, but it can also be a fierce enemy. Overzealous immune responses underlie a variety of diseases, including allergic conditions such as asthma and eczema, and autoimmune diseases like rheumatoid arthritis and lupus. The extraordinary complexity of the immune system makes these conditions challenging to understand and treat and are often difficult for patients to endure. But advanced scientific tools and technologies are lending unprecedented precision to this challenge—enabling researchers to deepen their knowledge about the multi-faceted nature of immune diseases and use those insights to design new and better treatments aimed at one or more molecular culprits underlying those conditions.

An ‘atomic-level’ view of the immune system

The immune system is a vastly complicated entity. Much of this complexity stems from the different types of immune cells, which interact with each other and with other cells and tissues of the body in distinct ways. Layer on top of that the biological variation that exists among different people and the task of finding the root causes of immune diseases becomes even more daunting.

To begin to unravel this complexity, Sanofi researchers are working to analyze disease biology at a more granular level than ever before. This includes methods for probing a person’s immune cells—one at a time—and scrutinizing the cells’ genomes or genetic makeup. For example, our scientists can read the activity levels of some 2,000 genes in a single immune cell and compare those readouts to other cells.

This paints a completely novel picture of what a disease looks like in individual patients or groups of patients,” said Frank Nestle, MD, Sanofi’s head of research in immunology and inflammation. 

This remarkable level of detail is turning up some important discoveries. First, different immune diseases may have similar molecular roots, so the biological signals that underlie one immune disorder could also be implicated in others. 

Different organs in the body, for example the skin, the lung, or the gut, can define how an immune disease manifests, but the biology underlying those different manifestations can be quite similar,” said Nestle.

This shared biology has important implications for drug development: for example, a drug developed to treat one type of condition could also provide therapeutic benefit for another disease. 

Another key finding to emerge from this atomic view of the immune system is that, in many cases, immune conditions have more than one biological cause. In order to develop effective treatments, we are finding that multiple treatment strategies must be combined into a single molecule, representing a new class of therapies known as multi-specific drugs.

If we want drugs that can effectively address the multifaceted nature of immune disease biology, then we’ll need the tools to engineer molecules that can interact with multiple targets,” said Nestle.

When one target is not enough

The vast majority of drugs in clinical use today are designed with the goal of interacting with a single molecule in the body, like an arrow hitting a bull’s-eye.

But now, we are pioneering ways to engineer drugs that can hit multiple bull’s-eyes at once, thanks to a confluence of groundbreaking technologies. 

One technology platform that is making this molecular tour de force possible involves the creation of therapeutic proteins called antibodies. These are a mainstay of modern medicine, but typically recognize just one molecular target. Sanofi Chief Scientific Officer Gary Nabel and his colleagues have pioneered a method to engineer antibodies that can neutralize three targets at once. Such three-in-one (or “tri-specific”) antibodies offer a promising new approach to the treatment of complex immune diseases.

Another new technology is also making it possible to design multi-specific drugs. This one is centered around a novel class of proteins structurally similar to antibodies yet smaller in size and more stable (Nanobodies®). These naturally-occurring proteins can be synthesized rapidly and at large-scale. Moreover, they can be readily combined, like beads on a necklace, to create multi-specific therapeutics. 

With the Nanobodies® platform, Sanofi is pursuing multi-specific therapeutics for a wide range of diseases, including immune and inflammatory conditions.

We are seeing a correlation with immunology and inflammation across multiple diseases. We are learning that diseases such as multiple-sclerosis, type 2 diabetes, neurodegenerative diseases, depression and cardiovascular diseases can be inflammation related,” said Nestle.

While these technologies for creating multi-specific drugs offer important benefits from a therapeutic perspective, they also provide some advantages in terms of drug development, making it possible to accelerate the development of novel treatments.

Our job is to be inspired and see what’s possible,” said Nestle.

SAGLB.IMM.19.10.1437 – OCTOBER 2019