The recycling collagen receptor uPARAP is a unique mediator of stromal drug delivery to carcinoma cells.

The genetic instability of cancer cells leads to cellular resistance against most targeted cancer drugs. Cancer-associated fibroblasts (CAFs) infiltrate all carcinomas and are genetically stable. Using antibody-drug conjugates (ADCs), we exploit the unique properties of a rapidly recycling endocytic receptor, uPARAP, to achieve a highly efficient CAF-mediated drug delivery and kill of carcinomas. This receptor is generally not present on carcinoma cells and is only expressed in a restricted group of mesenchymal cancer cell types which are sensitive to uPARAP-directed ADCs. However, we show that uPARAP is highly expressed in CAFs in all carcinoma types examined. This property is recapitulated in mouse xenograft carcinoma models. In these models, despite the absence of uPARAP on the carcinoma cells, uPARAP-targeting ADCs with clinically validated payloads MMAE and Dxd eradicated tumors with remarkable efficiency. Systemic treatment with anti-uPARAP ADC led to permanent eradication of tumors in mice carrying subcutaneous xenografts with human EBC-1 lung carcinoma cells. A pronounced repression of tumor growth and strongly increased mouse survival was also obtained with human HT29 colon adenocarcinoma cells, both when these tumors were growing subcutaneously and after homing of tumor cells to bone from the circulation. CAFs were largely refractory to ADC treatment and retained a high expression of uPARAP. uPARAP-expressing fibroblasts could also process an anti-uPARAP ADC in vitro and deliver the cytotoxic component to carcinoma cells. The current bystander mechanism may be exploited in the majority of the most prevalent solid cancers, thus making uPARAP an extraordinarily versatile target for ADC-based cancer treatment.