We have developed a new polymer based antibody drug conjugate (ADC) linker technology using the versatility of the RAFT process. The ability of RAFT to access polymers with a defined size, composition and architecture gives rise to this approach addressing key clinical and technical challenges with current ADC linker systems. Primarily amongst these is the ability to load multiple copies of a cytotoxic agent onto the polymer linker whilst still maintaining a single point of attachment to the antibody. This talk will describe synthesis of a range of stable water soluble polymers, and various synthetic approaches to construct a therapeutic antibody-polymer-drug conjugates, where the polymer acts as a linker for both a small molecule cytotoxic drug as well as a therapeutic protein (see Figure). In order to understand the influence of polymer structure, composition and size on biological performance, we report on the results of two, first in class, ADME studies. These studies assess the pharmacokinetics of a range of homo-polymer and co-polymer antibody-fragment conjugates, in animal models (seven RAFT polymer linkers and one control). All of the antibody fragment-polymer conjugates investigated had increased elimination phase half-lives over the PEGylated control, and although differences were observed within the circulating half-life between the conjugates arising from the different polymer compositions, the excretion volume is fairly consistent. This result confirms that this range of RAFT polymers are a suitable platform for delivery of proteins and targeted delivery of small molecule drugs. In addition, we have conjugated an ADME optimised, complex, high molecular weight, terpolymer containing a number of cytotoxic drugs, attached via cleavable linkers, to antibody fragments and the results of a drug-loaded polymer-antibody fragment conjugate in vivo efficacy study will be reported.

New polymer based linkers for antibody drug conjugates (ADC) for oncology applications

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.