Founder Q&A with Jeff Ravetch, MD, PhD
Jeff Ravetch, MD, PhD
Theresa and Eugene Lang Professor, Rockefeller University
Head, Leonard Wagner Laboratory of Molecular Genetics and Immunology
Challenge: Autoimmune diseases driven by multiple immune cell types
The pathology of many autoimmune diseases derives from interactions of multiple cell types including T cells and B cells/antigen presenting cells (APCs). Clinical evidence has shown that inhibitory checkpoint receptor antagonists can result in autoimmunity, suggesting that agonism may restore immune homeostasis.
New drug discovery approaches for autoimmune diseases
Seismic integrates machine learning with structural biology, protein engineering, and translational immunology to develop Dual Cell Bidirectional antibodies which simultaneously target multiple inhibitory pathways in more than one cell type to restore immune homeostasis in these diseases. These bidirectional antibodies agonize T cell checkpoint inhibitors, bind, and signal through, Fc receptors on APCs/B cells to prevent production of pro inflammatory cytokines and potentially inhibit pathogenic T cell, B cell and APC activity.
Expert perspective: Jeffrey V. Ravetch, MD, PhD
Dr. Jeffrey Ravetch is an academic founder of Seismic and a leading expert in the cell surface receptors that bind the Fc region of antibodies (FcR) and the mechanisms by which these receptors enable antibodies to mediate diverse biological activities. His work established the novel structural basis for Fc domain functional diversity and the pre-eminence of FcR pathways in host defense, inflammation and tolerance, describing novel signaling pathways to account for the paradoxical roles of antibodies as both promoting and suppressing inflammation. His work has been widely extended into clinical applications for the treatment of neoplastic, inflammatory, and infectious diseases.
In this installment of our Founders Q&A Series, Seismic’s Business Development Associate Rebecca Goydel, PhD, spoke with Dr. Ravetch about his work in immunology and Fc receptors, which offers expert insight into Seismic’s innovative approach to dysregulated cell-mediated immunity.
Rebecca Goydel:
Your work has changed the way we look at Fc receptors. How has the field evolved over the years to support the important role of Fc receptors in drug development?
Jeff Ravetch:
We continue to broaden the way the field looks at the Fc region of antibodies in general. For many years, the biological activity of an antibody has been attributed primarily to the Fab portion which has specificity for binding, while the Fc region of the antibody confers pharmacokinetic properties such as half life.
Historically, there has been a lot of resistance to the notion that the Fc domain is an integral part of the biological activity of the antibody.
If we jump ahead to 2000, that’s when the first antibodies emerged as therapeutics, in particular for oncology. They were developed based on their in vitro activities to arrest tumor growth. The presumption was that they worked by binding to a target that had specific cellular responses. It turns out from my lab’s studies back in 2000, that the activity for those antibodies was actually driven by cytotoxic capacity through the Fc, and that was Fc receptor driven. This understanding was the genesis of our interest in how therapeutic antibodies depend on Fc engagement.
It wasn’t until 2013 that the first antibodies with modified Fc to engage individual Fc receptors with some specificity were approved. Today, there are about half dozen Fc engineered antibodies with selective Fc receptor binding for enhanced FcR activity, and another half dozen or so where Fc modifications are made to reduce Fc receptor binding to reduce toxicity. That’s a good start. Now there’s a momentum in drug development, where anyone starting an antibody program considers both ends of the molecule. It has taken us twenty years to get to the point where it’s established to some degree. There’s still a lot to do and a great deal of opportunity.
Now that the Fc region is recognized as a key component for the biological activity of therapeutic antibodies, how readily is it being incorporated in drug development?
Indeed, Fc modification is now recognized as important in antibody drug development. But, there are still many areas to further understand the complexity of the Fc and Fc receptors. Throughout my career, I’ve focused on defining the role that the Fc region plays in biological processes that are antibody driven. It is complicated because there’s not one type of Fc region and Fc receptor, but multiple types of each. The combinatorial possibilities of those two components leads to hundreds of different Fc structures. How many of them are biologically relevant? What do they do? How are they regulated? Generally, there have been a few limited sets of mutations used to manipulate Fc activity, but they broadly impact Fc receptors. We still need to move the needle when it comes to stimulating Fc receptors selectively since they have different functions. This leaves a lot of room for improved therapies to be discovered and fill the large gap in this space.
Specifically, FcγRIIB is unique among Fcγ receptors, it has inhibitory activity and is the most abundantly expressed Fc receptor. It is present on almost all cell types that are involved in immune reactions and its level of expression is there to prevent inappropriate cellular activation, so it is well regulated. This makes it a useful target for therapies in the inflammation space. We know this balance of stimulating inhibitory receptor engagement is really key and if we can shift the equilibrium towards the inhibitory receptor, we have a chance at suppressing these inflammatory responses. Seismic’s Dual Cell Bidirectional program aims to address inhibitory receptor agonism by favoring FcγRIIB binding over its close relative FcγRIIA while agonizing inhibitory checkpoint receptors on T cells with the other end of the molecule to treat autoimmune diseases.
Checkpoint antagonists have emerged as an important class of immunotherapies in the last 10 years. What is your perspective of how the Fc and or Fc receptor binding fits in the landscape of current therapies?
This is an area that my lab is actively involved in. We’ve developed a flow chart for how one goes about developing an antibody that’s targeting a checkpoint receptor. Most checkpoint targets have both inhibitory as well as activating activity. What becomes a more important component? Is it blocking an inhibitory signal or agonizing a stimulatory pathway?
It’s tricky because there are different Fc requirements for antibodies targeting those two pathways, and that’s where choosing the right clinical model and indication becomes critical. For agonist pathways, we’ve begun to realize that antibodies are not terrific when it comes to cross-linking receptors, which is key for almost all receptor agonists. You need to have some way of bringing together multiple receptors (multimerizing) for the desired activity, and that’s where the Fc can be very valuable. And that’s of course one of the facets of Seismic’s Dual Cell Bidirectional product area, whereby engaging an Fc receptor, it can act as a scaffold to allow for multimerization.
What excites you the most about the work being done at Seismic?
Tim Springer called me and said he was starting a company that would be looking at pathways that impact the interaction of antibody Fc regions and Fc receptors, either to remove receptor engagement or optimize inhibitory receptor engagement. I thought that was a fabulous idea. When I was introduced to the team that was being assembled for this new company called Seismic, it was clear this was a group of people who knew what they were doing. I got the sense that this is a different model for a biotech company – one that’s built on the science, with an appreciation for the realities of getting across the finish line, so that was quite exciting.
The company’s work in engaging an inhibitory Fc receptor to act as a scaffold, allowing for multimerization, along with modulating the immune synapse between B and T cells, is really exciting and breaking new ground. For example, if you multimerize an inhibitory PD-1 antibody, you can create a stronger inhibitory signal. You can use an antibody with a modified Fc to accomplish this. The more exciting concept is that you can combine inhibitory activities from both the Fc receptor and checkpoint inhibitor pathways, and perhaps get an even greater inhibitory response with a bidirectional strategy, which is exactly what Seismic is working on.
Seismic is leveraging machine learning to accelerate drug discovery. From your perspective, how will machine learning contribute to and improve drug development in the area of immunology?
Historically, the way we used to do our optimization for Fc was basically trial and error. We had some receptors, we had some Fc variants, and we mixed and matched. We had no way of optimizing. When we hit upon something that worked, we said good enough, we’ll use it. But that’s obviously an older approach. Machine learning offers some very interesting possibilities and Seismic is leveraging this. We’ve started adopting machine learning in my own lab now too as we develop reagents that will specifically recognize various glycoforms of an IgG Fc and exploring how to take those glycoforms and manipulate them in ways that would be potentially therapeutic.
Machine learning is a powerful tool, and Seismic is deploying it strategically to move drug development in important new directions. The goal is to generate the correct immune synapse. In the case of Seismic, this includes desired checkpoint inhibitor agonism on T cells with the right Fcs included to target FcγRIIB receptors on B cells. Machine learning can aid in this to avoid the traditional trial and error. It’s an area that is ripe for rethinking and machine learning can contribute to future innovation.
