The work was collaboratively accomplished by CStone,
Presentation session: Multiple solid and hematological malignancies
Date:
Format: Late-breaking abstract (LBA)
Title: CS5001, a novel ROR1-targeting antibody drug conjugate (ADC) armed with tumor-cleavable-glucuronide linkers and pyrrolobenzodiazepine (PBD) prodrugs for hematological and solid malignancies
Speakers/Leading Principal Investigator: Dr.
CS5001 is an ADC composed of a human monoclonal antibody targeting ROR1, site-specifically conjugated with a proprietary cleavable-glucuronide linker to a prodrug of PBD dimer. Both linker and prodrug are selectively cleaved by the lysosomal -glucuronidase, which is overexpressed in many cancerous cells, to allow tumor-selective release of the DNA-crosslinking PBD dimer.
CS5001 bound specifically to human ROR1, but not ROR2. CS5001 has cross reactivity against mouse, rat and cynomolgus ROR1 at similar affinities. Upon binding, CS5001 was rapidly internalized by ROR1-expressing cancer cells. CS5001 demonstrated potent cytotoxicity towards ROR1 high expressing cell lines such as Jeko-1 (mantle cell lymphoma) and MDA-MB-231 (triple-negative breast cancer), with sub-nanomolar IC50 values. The growth inhibition activity of CS5001 was significantly correlated with ROR1 density in a panel of cancer cell lines.
CS5001 exhibited prominent antitumor activity in both Jeko-1 and MDA-MB-231 xenograft models in a dose-dependent manner. In addition, CS5001 demonstrated superior efficacy compared to an MMAE-based ROR1 ADC at equitoxic doses in the Jeko-1 model.
Dr.
CS5001 is a pre-clinical ADC completing IND enabling studies. CS5001 has a uniquely design tumor-cleavable linker that is conjugated to a LCB's proprietary pyrrolobenzodiazepine (PBD) prodrug. Only after reaching the tumor, the linker and prodrug are cleaved to release the PBD toxin, resulting in lethal DNA cross-links in cancer cells. The use of the linker plus PBD prodrug effectively helps addressing the toxicity problem associated with traditional PBD payloads, leading to a better safety profile. Additionally, CS5001 utilizes site-specific conjugation for a precise drug antibody ratio of 2 which enables homogeneous production and large-scale manufacturing.
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