Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates;

Authors: Martin Pabst, William McDowell, Anaïs Manin, Andrew Kyle, Nicolas Camper, Elena De Juan, Vimal Parekh, Felicity Rudge, Hiteshri Makwana, Terrence Kantner, Hemal Parekh, Aurelie Michelet, Xiao Bo Sheng, Gina Popa, Carolyn Tucker, Farzad Khayrzad, Derek Pollard, Katarzyna Kozakowska and Antony Godwin

Publication: Science Direct

First published: 27 February 2017

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5 mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

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