At the Antibody Engineering & Therapeutics conference in December 2020, Dr Glanville, CEO of Distributed Bio and Centivax, presented his exciting work on anti-GPCR therapeutics. GPCRs are traditionally tough therapeutic targets because they are located in membranes, making targeting and modifications challenging.
Dr Glanville explained that the work of Distributed Bio is ideal for examining the potential for GPCRs as therapeutics. The company has in recent years created technology to generate a larger repertoire of human antibodies than previously possible, using natural CDRs, allowing bigger fitness than synthetic antibodies because they have already passed the natural selection process for antibodies in the human body.
In 2018, Distributed Bio released SuperHuman 2.0 computationally optimized antibody library. Because the library is more diverse than previous antibody libraries, this allowed the group to examine GPCRs as potential therapeutic targets by having enough antibodies to explore. Dr Glanville then explained that extraction of GPCRs and selection is very challenging because GPCRs are membrane-bound and will be located in the lipid fraction of an assay. Distributed Bio focused on CXCR5 as a target of interest.
Distributed Bio’s strategy for targeting GPCRs consisted of parallel panning of the same target against the same library, followed by NGS in an automated method. The company then looked at the individual clones among NGS-identified anti-CXCR5 specific clones. The anti-CXCR5 antibodies were then confirmed by FACS.
The anti-GPCR IgGs were tested for their specificity and thermostability through functional screens. The screens were successful, selecting three potential binders for CXCR5 GPCRs.
These IgGs were optimized through Tumbler Optimization Platform technology combining computational and wet-lab approaches to infer optimal theoretical sequence.
The Tumbler platform helped to improve the functional activity of the lead clone 70-fold, leading to affinity-matured fully human anti-CXCR5 antibody, confirmed with in vitro assays.
Switching gears, Dr Glanville presented Distributed Bio’s work on another anti-GPCR antibody provided by the industry. He demonstrated that the Tumbler platform can be used on several anti-GPCRs antibodies.
Dr Glanville concluded his talk demonstrated the versatility of SuperHuman 2.0 and Tumbler Platform approaches in the design of multi-specific, bi-specific antibodies, cell therapies, CAR-T therapies and IgG design.
