Immunogenicity determination of Shark VNAR domains aids candidate selection

As next generation biologics such as novel scaffolds, antibody fragments and fusions progress towards the clinic the need to understand and predict potential immunogenicity issues is a crucial consideration. De-risking therapeutics at an earlier stage in development ultimately decreases more costly pipeline attrition at later stages of drug development. The Shark VNAR Development team (Elasmogen) have optimised both immunized and synthetic platforms to isolate novel therapeutic VNAR domains (the smallest binding site so far identified in nature). Elasmogen are currently undertaking an immunogenicity assessment of our lead half-life extension bio-tool, E06, with a view to increasing our understanding and to mitigate any downstream risks associated with adverse immune responses in any “first-in-man” studies. E06 is derived from an immunised shark and its crystal structure in the presence of antigen has been successfully determined. It binds with picomolar affinity to albumin and importantly extends the serum half-life of fused N-terminal and C-terminal binding domains from hours to days across rodent and non-human primate models of PK. Its predicted half-life extension in man is 19-20 days. In vivo studies to date, including a multi-dosed study in cynomolgous monkeys, have provided no evidence of immunogenicity. This aside, we felt it important to undertake a program of humanisation to minimise any downstream regulatory issues when utilising native non-human domains. This talk will cover our E06 humanisation strategy, in silico and in vivo immunogenicity data and work completed with ProImmune to date, to aid final humanised candidate selection for later stage pre-clinical development and eventual clinical studies.