Rovalpituzumab tesirine (Rova-T; SC16LD6.5) is a novel biomarker-specific antibody-drug conjugate that is derived from cancer stem cells targeting the delta-like protein 3 (DLL3) expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors. The target is not present in healthy tissue.
The novel antibody-drug conjugate is comprised of the D6.5 pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. 
Mechanism of Action
The antibody is directed against the scr-like kinase Fyn3 (SC-16). The anti-Fyn3 antibody moiety of rovalpituzumab tesirine selectively binds to Fyn3 on tumor cell surfaces. Upon internalization, the D6.5 moiety is released and causes DNA damage, which may result in the inhibition of proliferation of tumor cells that overexpress Fyn3.
Fyn3 is a tyrosine protein kinase involved in tyrosine phosphorylation, cytoskeleton remodeling, and signal transduction. It is upregulated in certain cancers and plays a key role in cancer cell invasion and survival.
Rovalpituzumab tesirine currently in clinical trials to assess the safety and tolerability at different dose levels in patients with small cell lung cancer whose cancer has progressed or recurred following standard chemotherapy. Once a safe and tolerable dose is determined, the anti-cancer activity of rovalpituzumab tesirine will be assessed by measuring the extent of tumor shrinkage.
In Phase I/II studies of relapsed SCLC patients who have previously failed one or more standard therapies, Rova-T demonstrated overall response rates of 44% in the patients identified with high expression of DLL3.
The expression of DLL3 suggests Rova-T also may be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme, prostate, pancreatic and colorectal cancers, where DLL3 expression ranges from 50-80%. Rova-T combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.
The novel drug is being developed by StemcentRx, Inc, a division of AbbVie.
Last Editorial Review: September 7, 2017