In this interview, John Desjarlais, Chief Scientific Officer of Xencor, outlines the company’s leadership in Fc engineering and its expansion into bispecific antibody technologies. He describes Xencor’s portfolio of Fc modifications that boost affinity for various Fc gamma receptors, applied across oncology, autoimmune, and other disease areas. Desjarlais explains the engineering of Fc heterodimers that enable bispecific antibodies with distinct selectivities on each arm, highlighting a Phase 2 anti‑CD19 program with an enhanced Fc for inhibitory FcγR in autoimmune disease, a licensed high‑ADCC anti‑CD19 antibody in Phase 2 with Amorphosis, and the upcoming launch of two bispecifics. He discusses key challenges in bispecific development, including manufacturability, affinity balancing, and defining a unique niche amid intense competition. The conversation also explores the novel biology enabled by bispecifics—such as T‑cell recruitment via CD3 targeting, bispecific checkpoint blockade, and potential applications in infectious disease and resistant tumors. Desjarlais emphasizes the value of industry conferences for staying abreast of antibody technology advances and their therapeutic applications.
Chapters
My name is John Desjarlais. I'm the Chief Scientific Officer at Xencor. Over time, Xencor has emerged as one of the leading Fc engineering companies. So we, we have a whole suite of different Fc technologies that enhance affinity for various Fc gamma receptors, and we apply those to, you know, oncology, autoimmune diseases, and and various other diseases. And then more recently, we've developed one of the leading bispecific technologies by engineering Fc heterodimers that enable us to make, to put, you know, two different selectivities on either side of the Fc to arrive at a novel type of bispecific antibody. Farthest advanced lead is a Phase 2 program. It's an anti-CD19 with an enhanced Fc for the inhibitory Fc gamma receptor that's being developed in autoimmune diseases. Amorphosis is actually developing. They're now in phase 2 with an antibody, an anti-CD19 with high ADCC that we licensed to them back in 2010. And then we'll have our first 2 bispecifics in the clinic starting next year. So there's a lot of challenges. I mean, you know, I think the, you know, the new wave is really bispecifics, you know, multi-selectivity and, you know, One of the more important challenges there is being able to manufacture those bispecifics easily, and also just to figure out exactly how to combine the two selectivities in the right way with the right affinities to get the properties that you want. And then embedded in that challenge is the fact that there are dozens and dozens of companies trying to all do the same thing. And so I think one of the real big challenges is figuring out what is going to be your niche. What do you have that's novel compared to what any number of pharma companies are also doing? It's kind of what we're doing and what a lot of other people are doing. It's multi-selectivity. And what's exciting about it is you get to, when you have a bispecific technology, you get to combine two targets that don't naturally get coupled in the immune system and see sometimes crazy things happening. You can make fairly dramatic things happen. For instance, if you recruit a T cell by using a CD3 bispecific coupled with a tumor antigen target, we're starting now to explore also bispecific checkpoint blockade. And we're seeing novel biology emerge when you do those kinds of things. So that's, that's what's exciting is, is, you know, getting to follow, you know, brand new biology. You know, I think there's kind of an unmet need in, you know, infectious disease that hasn't really been, you know, targeted heavily by pharma. And I think there's some emerging results recently that are getting kind of exciting there. And then there's, you know, there's a lot of unmet needs still in oncology, specific types of tumors, you know, tumors that don't really respond to checkpoint blockade and trying to figure out, you know, how do you actually make something significant happen in those types of tumors. I like to come every year because it gives me an opportunity to see all of the things that are going on in terms of antibody technology development, but also in their application. It allows me to see like a wide swath of what's going on in terms of application to different indications, right? So I see not only the technologies but also what's going on, you know, kind of some cutting-edge stuff going on in terms of different diseases.
