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

Authors: Pabst M1, McDowell W2, Manin A2, Kyle A2, Camper N2, De Juan E2, Parekh V2, Rudge F2, Makwana H2, Kantner T2, Parekh H2, Michelet A2, Sheng X2, Popa G2, Tucker C2, Khayrzad F2, Pollard D2, Kozakowska K2, Resende R2, Jenkins A2, Simoes F2, Morris D2, Williams P2, Badescu G2, Baker MP2, Bird M2, Frigerio M3, Godwin A2.

Publication: J Control Release

First published: 10 May 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 0.5mg/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.

Full paper available at:

Interested in our services? Get In Touch