Zymeworks-GSK Collaboration Leads To Design and Validation of a Novel Engineered, FcγRIIb-Selective Fc Platform for Therapeutic Antibody Development

Zymeworks and GSK have been collaborating for several years to identify and validate a new platform for developing antibodies that selectively target the receptor FcγRIIb. The data and outcomes from this research were presented at PEGS Europe, Protein & Antibody Engineering Summit, on November 3 in Barcelona and virtually. 

There are many subtypes of Fcgamma receptors (FcγRs) but FcγRIIb is the only inhibitory receptor and is involved in many functions including B cell activation, innate immune responses, peripheral tolerance, and scavenging of immune complexes. In order to enable antibody functions that leverage some of these immune functions and avoid the undesirable effects of interacting with the other subtypes of FcγRs, the team sought to engineer antibodies that are selective to FcγRIIb as a new therapeutic platform.

The team at Zymeworks used a rational structure-guided computational design approach, and leveraged Zymeworks’ proprietary Azymetric™ platform, to design a family of engineered antibodies with asymmetric point mutations and/or asymmetric loop insertions. These antibodies showed not only enhanced and selective binding to FcγRIIb, but also provided a range of affinities for this receptor. In addition, they displayed similar stability to the normal antibodies, a range of C1q affinities, normal binding to FcRn, and low predicted immunogenicity.

The applications of FcγRIIb-selective antibodies include enhancement of antibody activities such as:

  1. Agonism for antibodies that recognize members of the tumor necrosis factor receptor family;
  2. Inhibition of B-cells (for example, using antibodies that recognize CD19); and,
  3. Clearance of soluble antigens, such as IgE.

With these applications in mind, the team at GSK performed functional characterization of selected members of the family of Zymeworks engineered antibodies and showed that the library provides FcγRIIB-selective options which optimize antibody activity for particular therapeutic applications, while maintaining good developability characteristics and compatibility with different antibody formats and antibody engineering technologies.

The data presented at PEGS Europe represent a large body of work that required collaboration amongst a significant number of people from both the Zymeworks and GSK teams. The research from this collaboration has the potential to enable the development of novel, FcγRIIb-selective therapeutics in oncology and other therapeutic areas.