The receptor tyrosine kinase ROR1 is a cell-surface onco-fetal protein expressed on a variety of solid tumours and haematological malignancies, which has limited expression on normal adult tissue. A functional role for ROR1 in tumorigenesis and disease progression has been demonstrated in a number of cancer indications. ROR1 is also involved in mediating drug resistance (for example to chemotherapies as well as to the targeted therapy T-DM1), activation of YAP/TAZ signalling and up-regulation of BMI-1. Consistent with this pleiotropic role, increased ROR1 expression correlates with poor clinical outcome in a number of cancer indications including triple negative breast cancer, ovarian cancer and lung adenocarcinoma. As a result, ROR1 has emerged as a highly attractive target for cancer therapy, and its limited expression on normal tissues make it particularly well suited for antibody and protein-drug conjugate (ADC and PDC) approaches. This has been fuelled by recent Phase I clinical data for the ROR1 ADC, VLS-101, in patients with advanced MCL and DLBCL and the potential of ROR1-targeting drug conjugates for the treatment of ROR1+ solid tumour indications. We report the development of novel, differentiated protein drug conjugates targeting ROR1 based on Variable New Antigen Receptor domains (VNARs). VNARs are the smallest antigen binding domain in the vertebrate kingdom and their small size and modular nature offer a number of potential benefits over full-length antibodies as the payload delivery vehicle in PDC approaches. We have applied our VNAR drug discovery platform, which includes novel linker-toxin combinations, to the development of potent and selective ROR1 targeting PDCs that are highly efficacious in ROR1+ patient derived xenograft (PDX) models of cancer. Homogenous drug conjugates were generated by Fc-fusion reformatting of ROR1 binding VNARs, and novel cleavable linker-toxin conjugates attached in a site-specific fashion. By exploiting proprietary crystal-structure information, a structure-guided approach was used to deliver VNAR-hFc drug conjugates with optimised drug-like properties. Though iterations of this approach, lead PDCs have been developed which cause potent ROR1-dependant killing of selected cancer cell-lines and elicit complete and durable regressions in PDX models of TNBC at doses that are very well tolerated. As the lead Candidate progresses toward clinical development, we anticipate that this excellent pre-clinical profile will translate to a highly differentiated product for the treatment of both solid tumor and haematological cancer indications. In addition, the flexible formatting accessible using our drug discovery platform has allowed us to readily access ROR1-targeting bi-paratopic and bi-specific therapeutic formats.

Citation Format: Graham Cotton, Jennifer Thom, Paul Trumper, Stacey Bell, Mark Wappett, Caroline Barelle, Marina Kovaleva, Andrew Porter, Estelle McLean, Chiara Saladino, Aidan McCann, Aaron Cranston, Tim Harrison. Development of a next generation ROR1 targeting Protein Drug Conjugate (PDC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB096.