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 30 Limpet Haemocyanin (KLH) permits the evaluation of immunomodulatory investigational 31 medicinal product (IMP) pharmacology prior to the recruitment of patient populations. 32 Despite widespread use, no standardized approach to the design and conduct of such 33 studies has been agreed. The objective of this systematic review was to review the 34 published literature where KLH was employed as a challenge agent, describing 35 methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. 36 We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies 37 employing KLH challenge in humans between 1 January 1994 and 1 April 2022. We 38 described key study features, including KLH formulation, dose, use of adjuvants, route of 39 administration, co-administered IMPs and endpoints. Of 2421 titles and abstracts screened, 40 46 met the inclusion criteria including 14 (31%) early phase trials of IMP, of which 10 (71%) 41 targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of 42 the humoral response to KLH, suggesting limited specificity of this endpoint. Two early 43 phase IMP studies (14%) described the response to intradermal re-challenge (delayed type 44 hypersensitivity). Challenge regimens for IMP assessment were often incompletely 45 described, and exhibited marked heterogeneity, including primary KLH dose (25-fold 46 variation: 100-2500mcg), KLH formulation, and co-administration with adjuvants. 47 Methodological heterogeneity and failure to exploit the access to tissue-level mechanism 48 relevant endpoints afforded by KLH challenge has impaired the translational utility of this 49 paradigm to-date. Future standardisation, characterisation and methodological 50 development is required to permit tailored, appropriately powered, mechanism-dependent 51 study design to optimise drug development decisions