Anti-Ly6E (RG7841 / DLYE5953A) Drug Description

RG7841, also known as RG-7841, DLYE5953A and Anti-Ly6E, Lymphocyte antigen 6 complex, locus E,  is an antibody-drug conjugate being developed by Genentech / Roche in collaboration with Seattle Genetic.

The antibody-drug conjugate, composed of an antibody against the tumor-associated antigen (TAA) lymphocyte antigen 6 complex locus E (Ly6E) is, via a protease-labile linker MC-vc-PAB, linked to the potent anti-mitotic agent monomethyl auristatin E (MMAE).[1][2]

Following intravenous administration, the antibody moiety targets and binds to Ly6E expressed on tumor cells. Upon binding and internalization, the cytotoxic agent is released and kills, through an as of yet unknown mechanism of action, the Ly6E-expressing cancer cells.

Promising target
In early development, researchers used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising target for the development of an antibody-drug conjugate. They developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models.

Using in silico approaches, researchers found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. Immunohistochemistry (IHC) analysis revealed high LY6E protein expression in a number of tumor types, including breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Furthermore, characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models.

Clinical trial
In an open-label, 3 + 3 dose-escalation study researchers assessed safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of RG7841 / DLYE5953A administered intravenously every 21 days (q3w) in patients with advanced or metastatic solid malignancies that had progressed on standard therapy. The administered dose was 2.4 mg/kg has acceptable tolerability with manageable adverse events (AE) and promising preliminary anti-tumor activity in solid tumors. [2]

Based on pre-clinical and ongoing clinical research, LY6E is a highly promising molecular ADC target for a variety of solid tumor types with current unmet medical need.

Clinical trial identification: NCT02092792.

Reference
[1] Asundi J, Crocker L, Tremayne J, Chang P, Sakanaka C, Tanguay J, Spencer S, et al. An Antibody-Drug Conjugate Directed against Lymphocyte Antigen 6 Complex, Locus E (LY6E) Provides Robust Tumor Killing in a Wide Range of Solid Tumor Malignancies. Clin Cancer Res. 2015 Jul 15;21(14):3252-62. doi: 10.1158/1078-0432.CCR-15-0156. Epub 2015 Apr 10.
[2] Modi S, Eder JP, Lorusso P, Weekes C, Chandarlapaty S, Tolaney SM, McLaughlin J, et al.  A phase I study evaluating DLYE5953A, an antibody-drug conjugate targeting the tumor-associated antigen lymphocyte antigen 6 complex locus E (Ly6E), in patients (Pts) with solid tumors. Annals of Oncology 27 (Supplement 6): vi114–vi135, 2016 doi:10.1093/annonc/mdw368.1