Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance

• DOI: 10.3389/fphar.2022.764540
• Publication Date: 2022-06-17T07:01:55Z
• Authors: Nick Evans; Ruslan Grygorash; Paul Williams; Andrew Kyle; Terrence Kantner; Ravindra Pathak; XiaoBo Sheng; Fabio Simoes; Hiteshri Makwana; Ricardo Resende; Elena de Juan; Alan Jenkins; David Morris; Aurelie Michelet; Frances Jewitt; Felicity Rudge; Nicolas Camper; Anaïs Manin; William McDowell; Martin Pabst; Antony Godwin; Mark Frigerio; Matthew Bird
• Keywords: Linker; Conjugate

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals date. As the field matures, much attention has focused upon key factors required produce safe and efficacious ADCs. Recently role that linker-payload reagent design on properties of ADCs been highlighted an important consideration for developers. We investigated effect incorporating hydrophilic macrocycles into structures in vitro vivo behavior Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized a panel cyclodextrins crown ethers integrated via glutamic acid branching point. Brentuximab was selected model antibody drug-to-antibody ratio (DAR) 4 prepared biological evaluation. In vitro, showed broadly similar potency (range: 16-34 pM) comparable Adcetris® (16 pM). vivo, cyclodextrin containing greater efficacy than most variant (incorporating 3'-amino-α-cyclodextrin component) matched 24-unit poly(ethylene glycol) (PEG) comparator. The also displayed enhanced compared Adcetris®, active (containing 1-aza-42-crown-14 macrocycle) superior analogous ADC larger PEG chain. summary, we demonstrated can be effectively incorporated offer potential alternatives established drug-linker architectures.