In vivo human keyhole limpet haemocyanin challenge in early phase drug development: A systematic review

Experimental exposure of healthy volunteers to the T-cell dependent neoantigen Keyhole Limpet Haemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to review the published literature where KLH was employed as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies employing KLH challenge in humans between 1 January 1994 and 1 April 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co-administered IMPs and endpoints. Of 2421 titles and abstracts screened, 46 met the inclusion criteria including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this endpoint. Two early phase IMP studies (14%) described the response to intradermal re-challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25-fold variation: 100-2500mcg), KLH formulation, and co-administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue-level mechanism-relevant endpoints afforded by KLH challenge has impaired the translational utility of this paradigm to-date. Future standardisation, characterisation and methodological development is required to permit tailored, appropriately powered, mechanism-dependent study design to optimise drug development decisions.