Guiding antibody-drug conjugates from circulation to cytoplasm

New mechanisms controlling ADC payload release provide handles to boost the modality's efficacy

A linchpin for the efficacy of antibody-drug conjugates is ensuring the payload travels from the circulation, to the endosomal pathway, and ultimately into the cytoplasm. A new study by Stanford University researchers uncovers biological pathways that control these steps, pointing drug developers towards combination therapies to optimize ADC delivery.

After internalization by target cells, the therapeutic payload must be separated from the tissue-targeting mAb to which it is connected. While some ADC developers have opted to connect payload and antibody via linkers that can be cleaved by enzymes in the tumor microenvironment or triggered by certain conditions in endosomes, others have chosen to use non-cleavable linkers that keep antibody and payload intact until the antibody is digested in the lysosome.

The latter are thought to be less prone to off-target effects in circulation, but the trade-off is a risk of lower efficacy, as some ADCs are recycled back to the membrane and don't make it to the lysosome (see “ADCs' Inflection Point”).

In a Nature Chemical Biology study, the Stanford group found a way to increase lysosomal trafficking of ADCs with non-cleavable linkers, increasing the likelihood that the payload is released and can exert its therapeutic effects on the cell.

The group used a CRISPR-Cas9-based screen to identify genetic perturbations that increased ADC-dependent tumor cell death. The screen identified two genes that regulated synthesis of sialic acid, a sugar incorporated into proteins and lipids in the cell membrane.

Additional cell culture studies suggested that sialic acid decreases the amount of ADC that enters the lysosome. Inhibiting the enzymatic addition of sialic acid to proteins and lipids with a tool compound increased lysosomal entry of two ADCs with non-cleavable linkers, payload escape into the cytoplasm and cell death compared with ADC treatment alone.

The two tested ADCs were the anti-HER2 therapy Kadcyla ado-trastuzumab emtansine from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY), and an anti-CD22 ADC created by the researchers.

Through the CRISPR-Cas9 screen, the authors also identified novel regulators of lysosome formation, including the lysosomal transporter protein SLC46A3, and suggest expression of these proteins could predict responses to ADCs with non-cleavable linkers. The authors cited a previous study from AstraZeneca plc (LSE:AZN; NYSE:AZN) showing high SLC46A3 expression correlated with resistance to ADCs with non-cleavable linkers in patient-derived xenograft models and primary bone marrow samples.

In an associated New & Views article in Nature Chemical Biology, Peter Senter and Heather Van Epps of ADC company Seattle Genetics Inc. (NASDAQ:SGEN) said the work by the Stanford group "will prove useful towards developing optimized therapeutics." Senter is VP of chemistry and Van Epps is associate director of antibody discovery.

The Stanford team did not respond to a request for comment in time for publication.

Targets: HER2 (EGFR2; ErbB2; neu) - Epidermal growth factor receptor 2; SLC46A3 - solute carrier family 46 member 3

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