Abstract 1042: Development of AEB1102, an engineered human arginase 1 for patients with solid tumors
Authors: Rowlinson Scott W. , Alters Susan E. , Agnello Giulia , Tyler Joseph , Lowe Ann , Okamoto-Kearney Mauri , Johnson Dale , Stone Everett , Georgiou George , Lowe David G. 
Published: July 2016

Abstract
Introduction: Tumor dependence on specific amino acids for survival and proliferation is well recognized and has been exploited effectively with the use of Asparaginase for the treatment of Acute Lymphoblastic Leukemia. Decades of research have led to an understanding of tumor L-Arginine (L-Arg) dependence, with functional expression of the three enzymes of the L-Arg biosynthetic pathway: Ornithine Transcarbamylase (OTC), Argininosuccinate Synthase (ASS1) and Argininosuccinate Lyase (ASL) being required to convert ornithine to L-Arg. In a variety of tumor types, silencing of one or more of these enzymes disables endogenous L-Arg synthesis forcing a reliance on the extracellular pool of L-Arg for tumor survival and proliferation. This mechanism has been confirmed with Arginine Deiminase (ADI-PEG) and pegylated wild-type Arginase I (BCT-100). Aeglea Biotherapeutics Inc. has developed an alternative approach using a bioengineered human PEGylated Arginase I with enhanced pharmacological properties. Replacement of manganese, the natural metal co-factor in wild-type human Arginase I, with cobalt confers improved catalytic activity and serum stability. The resulting product candidate (AEB1102) displays highly favorable PK/PD properties, and is expected to be naturally tolerated by the human immune system as no protein modifications have been introduced.
Experimental Procedures and Results: Non-clinical dose range finding and GLP toxicology studies were performed with AEB1102 in monkeys and mice. Bioanalytical assays detecting L-Arg and AEB1102 enzyme activity were used to monitor PD/PK in the dose range finding studies with these results subsequently being used to design the toxicology studies. Subsequent toxicology studies identified an NOAEL in both species at a dose that is predicted to translate to significant sustained reduction of L-Arg serum levels with weekly intravenous dosing. To determine tumor types most likely to respond to AEB1102 expression profiling of OTC, ASS1 and ASL was performed using in situ hybridization on multiple tumor histologies. Melanoma was identified as a tumor type likely to respond to AEB1102 owing to a significant reduction in ASS1 expression. Non-clinical in vivo studies using the A375 melanoma xenograft as well as melanoma PDx models confirm sensitivity to AEB1102, weekly dosing resulted in a significant delay in tumor growth and improved survival.
Conclusion: Non-clinical activities required to support the IND submission of AEB1102 for solid tumors were successfully executed, enabling the Phase 1 study to be initiated in October 2015. Translational work profiling the expression of OTC, ASS1 and ASL has identified melanoma as a relevant tumor type to pursue in future clinical studies.
Citation Format: Scott W. Rowlinson, Susan E. Alters, Giulia Agnello, Joseph Tyler, Ann Lowe, Mauri Okamoto-Kearney, Dale Johnson, Everett Stone, George Georgiou, David G. Lowe. Development of AEB1102, an engineered human arginase 1 for patients with solid tumors. [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 1042.