Abstract 2690: A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma

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Abstract Activated ALK by mutation or amplification is a validated therapeutic target in a subset of patients with high-risk neuroblastoma, and tyrosine kinase inhibitors are being developed to abrogate ALK signaling (Bresler et al, 2014). Native ALK is expressed on the surface of the majority of neuroblastoma tumors, but not on normal tissue, giving it properties of a tumor antigen. We hypothesized that ALK-targeted antibodies may be useful in neuroblastoma as single-agent immunotherapy or in combination with small-molecule ALK inhibitors - especially where mutations reduce kinase inhibitor sensitivity. In this work, an anti-ALK monoclonal antibody (anti-ALK2) was conjugated to a cytotoxic agent (ALK2-ADC) and its anti-tumor activity was investigated in a panel of extensively characterized human neuroblastoma cell lines (n = 10) harboring wild type and mutant ALK. Cell surface ALK was quantified using flow cytometry and revealed differential antigen expression. Using in vitro growth inhibition assays, there was evidence for a dose-dependent cytotoxicity to neuroblastoma cells at subnanomolar concentrations that correlated with ALK expression and was independent of underlying mutation status. In order to evaluate the therapeutic potential of ALK2-ADC in vivo, mice bearing Felix-patient-derived xenograft (PDX) tumors, containing the third most common ALK mutation (R1245C), were used to demonstrate that ALK2-ADC led to a significant reduction in tumor growth compared to unconjugated antibody and a control ADC (p<0.0001). Although ALK2-ADC binds potently to mouse ALK as well as human ALK, doses of up to 10 mg/kg in the rodent model appeared to be well tolerated with no overt toxicity noted. Additional in vivo studies are ongoing to assess the antitumor potential of the ADC in a broader range of ALK-expressing neuroblastoma models. Thus, targeting human ALK-expressing with an ALK antibody-drug conjugate demonstrated early signs of favorable efficacy and tolerability supporting future development of this approach as a potential novel therapeutic for patients with neuroblastoma. Citation Format: Renata Sano, Kateryna Krytska, Colleen Larmour, Gwenda F. Ligon, Jay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Gerald McMahon, Diego Alvarado, Yael P. Mosse. A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2690.