The Zebra Platform –
A next-gen Approach to Exploiting Combinatorial Antibody or Peptide Libraries
The new Zebra platform unlocks the immense and inherent diversity of existing combinatorial antibody and peptide libraries in a novel and powerful next-gen mode that :
• permits direct screening of antibody or peptide libraries in function based assays for either agonists or antagonists of desired drug targets
• allows direct screening for antibodies or peptides that induce morphogenic or phenotypic changes in any primary cultured cell such as stem cells or progenitor cells.
• may be used to derive therapeutic candidates for new and or previously hard to drug targets.
• may be used to derive “Bio-differents TM’ or pheno-copies of blockbuster agonist biologics (such as erythropoietin – EPO, or other hematopoietic growth factors).
Bio-differents are fully human antibody biologic molecules being developed by Zebra that have the identical biological function of established therapeutic biologic drugs but have no structural similarity. Such molecules open up opportunities for new intellectual property, avoid all patent estates of existing biologics and offer protein engineering opportunities that can lead directly to short or long acting versions of the existing biologic as desired.
Fig 1. Schematic of the Zebra platform as employed to derive a scFv 'phenocopy' (Bio-different) of the hematopoietic growth factor erythropoietin (EPO).
Zhang et al. PNAS | September 25, 2012 | vol. 109 | no. 39 | 15733
Fig. 1. Scheme for selection of antibody agonists from combinatorial libraries. Antibodies that bound EpoRwere selected from a combinatorial antibody library displayed in phage by affinity-based selection. The antibody genes from the selected phage were cloned into lentiviral vectors to allow phenotypic selections afterinfection of eukaryotic cells and integration of the antibody genes into the genome. The transduced cellswere plated in methylcellulose agar such that the secreted antibodies were trapped around the cells producingthem. The colonies that formed were harvested using a micromanipulator, and the antibody genes were recovered by PCR. The PCR products were cloned and sequenced, and the respective antibodies or antibody combinations were tested for their activity. The active antibodies were expressed in mammalian cells and purified for further characterization.
Breadth of Zebra Platform Utility
The versatility of the Zebra technology allows it use:
• across all disease areas
• ready derivation of agonist therapeutic candidate biologics
• unbiased discovery of antibodies or peptides that can drive cellular differentiation, prevent cell death from multiple
insults, induce cellular proliferation of stem or progenitor cells
• discovery of novel intracellular drug targets for small molecule targeting
• rapid development of “large molecule tools” for target validation of small molecule Rx areas
Zebra’s Two- Pronged Pipeline Strategy
Zebra’s near term focus is to exploit it’s proprietary platform to derive and develop:
• A pipeline of novel biologics for and with partners under both licensing and R&D collaboration agreements.
• A pipeline of Bio-differents, initially with a focus on out-licensing , with select products later being developed to mid-stage clinical development by Zebra