ABSTRACT
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.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Oligopeptides , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Drug Design , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Immunoglobulin G/chemistry , Immunoglobulin G/therapeutic use , Ki-1 Antigen/immunology , Mice, SCID , Neoplasms/drug therapy , Neoplasms/pathology , Oligopeptides/chemistry , Oligopeptides/pharmacokinetics , Oligopeptides/therapeutic use , Polyethylene Glycols/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
This article explores science journalism in the context of the media competition for readers' attention. It offers a qualitative stylistic perspective on how popular journalism colonizes science communication. It examines a sample of 400 headlines collected over the period of 15 months from the ranking of five 'most-read' articles on the website of the international magazine New Scientist. Dominant lexical properties of the sample are first identified through frequency and keyness survey and then analysed qualitatively from the perspective of the stylistic projection of newsworthiness. The analysis illustrates various degrees of stylistic 'hybridity' in online popularization of scientific research. Stylistic patterns that celebrate, domesticate or personalize science coverage (characteristic of popular journalism) are intertwined with devices that foreground tentativeness, precision and informativeness (characteristic of science communication). The article reflects on the implications of including various proportions of academic and popular styles in science journalism.
Subject(s)
Communication , Journalism , Periodicals as Topic , Public Opinion , Community Participation , Information Dissemination , WritingABSTRACT
The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable of rebridging reduced (native) antibody interchain disulfide bonds has been previously shown to produce a homogeneous and stable conjugate with a drug-to-antibody ratio (DAR) of 4 as the major product. Here, we further investigate the potency of the DAR 4 conjugates prepared by bis-alkylation by comparing to lower drug loaded variants to maleimide linker based conjugates possessing typical mixed DAR profiles. Serum stability, HER2 receptor binding, internalization, in vitro potency, and in vivo efficacy were all evaluated. Greater stability compared with maleimide conjugation was observed with no significant decrease in receptor/FcRn binding. A clear dose-response was obtained based on drug loading (DAR) with the DAR 4 conjugate showing the highest potency in vitro and a much higher efficacy in vivo compared with the lower DAR conjugates. Finally, the DAR 4 conjugate demonstrated superior efficacy compared to trastuzumab-DM1 (T-DM1, Kadcyla), as evaluated in a low HER2 expressing JIMT-1 xenograft model.
