PURPOSE - New cancer-specific antigens are required for the design of novel antibody drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy.
EXPERIMENTAL DESIGN - Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen.
Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADC comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a non-cleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood.
RESULTS - ENPP3 was highly expressed in clear cell renal cell carcinoma (ccRCC): 92. 3% of samples were positive and 83. 9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinomas (prCC) and hepatocellular carcinomas (HCC) samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different RCC xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death.
CONCLUSIONS - AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a Phase I clinical trial.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Nov 20 [Epub ahead of print]
Fernando Donate, Arthur Raitano, Kendall Morrison, Zili An, Linette Capo, Hector Avina, Sher Karki, Karen Morrison, Peng Yang, Jimmy Ou, Ryuichi Moriya, Yuriy Shostak, Faisal Malik, Rossana Nadell, Wendy Liu, Daulet Satpayev, John Atkinson, Ingrid B J Joseph, Daniel S Pereira, Pia M Challita-Eid, David R Stover
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