New antibody discovery platform could help accelerate CAR-T therapeutic development

In a paper published in the Journal of Biological Chemistry​​​, OXGENE scientists used the self-labelling integral membrane (SLIM) protein discovery system to identify a panel of novel antibodies against the oncogenic target epithelial cell adhesion molecule, which remained in its native configuration within the cell membrane.

They said they were able to further demonstrate the functionality of these antibodies in killing cancer cells, when used as a targeting domain of CAR-T cells, thereby “validating the potential of this technology for the discovery of new CAR-T or antibody therapeutics.”

Dr Nathan Robertson, group leader of OXGENE’s antibody discovery team said: “Unlike other mammalian display systems, the SLIM platform is compatible with libraries of up to a billion variants — a ~100-fold increase compared to libraries used in traditional mammalian display. Furthermore, the in-built compatibility with downstream development increases the chances that antibodies discovered using SLIM display will be both physiologically relevant and suitable for manufacture.”​

Antibody discovery ​

Discovering antibodies against integral membrane proteins can be challenging as most of the protein sits within the membrane itself, leaving reduced surface exposed epitopes above the cell membrane for antibody binding, said the biotech.

Many antibody discovery systems rely on purifying and/or linearizing the target protein first, but  antibodies discovered using this approach can often bind to irrelevant parts of the purified protein, rather than extracellular domains, or to linear epitopes within the extracellular domain that are occluded in its native conformation.

“OXGENE’s SLIM mammalian display system is designed to overcome these obstacles by discovering antibodies against complex membrane proteins in their native configuration.”​

The company outlined how, in SLIM display, a target membrane protein and a library of potential binders are expressed in the same mammalian cells. These then progress through multiple rounds of enrichment and purification to obtain a single clone expressing a single-chain variable fragment that can bind the target antigen, said the developer.

SLIM display implements a specific strategy to reduce false positives and ensures that confirmed binders only target physiological epitopes, it continued.

The platform also uses Chinese hamster ovary cells throughout discovery, so binders are far more likely to be compatible with downstream processing, it said.

Licensing agreements 

In May last year, OXGENE reported that it had more than doubled its annual revenue as its financial year came to a close, with notable strategic licensing agreements secured.

The scene was set, it said back then, for industry wide adoption of its leading AAV and lentiviral transient gene therapy production technologies by licensing to both CMOs and therapeutics manufacturers across the globe.

In April 2020, OXGENE announced a partnership with Fujifilm Diosynth Biotechnologies (FDB) or the use of its AAV production platform, comprising optimized helper, Rep/Cap and gene of interest plasmids, used in combination with a clonal suspension HEK293 cell line, for customers engaged in process development and GMP manufacture of gene therapies at FDB’s College Station, Texas site.