Abstract 4918: Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy

Introduction: Cancer immunotherapy is the emerging paradigm in the search for a cure for cancer. AT1965 is a novel therapeutic that demonstrates remarkable anti-tumor activity across different preclinical tumor models, mediated through the activation of B-cells. In this study, we have evaluated the metabolism, pharmacokinetics (PK) and toxicity of AT1965 in rodent and non-rodent species. Methods: AT1965 metabolism was studied in rodent, canine and primate liver microsomes. The PK of AT1965 was determined in 4T1 tumor bearing female Balb/c mice; female Sprague Dawley rats and female Beagle dogs at a variety of doses and schedules following single intravenous (i.v) injections. The extent and duration of the exposure was monitored over 120 hours in mice and rats, and till 192 hours in dogs, post dosing. Concentrations of AT1965 in plasma samples were determined either by LC-MS/MS or Atomic Absorption Spectroscopy. The toxicity of AT1965 in male and female Sprague Dawley Rats following single dose i.v. administration of 43.7, 87.4 and 174.8 mg/kg dosage of AT1965 were examined. During toxicity studies, clinical health status was observed daily for 14 days after treatment, followed by necropsy. Results: AT1965 metabolism evaluated in mouse, rat, dog, monkey and human liver microsomes indicated high stability across all species. PK studies reveal that AT1965 exhibited a high exposure, slow systemic clearance and a proportional increase in dose normalized exposure across species. The elimination half-life (T1/2) varied from 34-40 hours in tumor-bearing mice to 29-44 hours in rats and ~ 66 hours in dogs. The excretion of AT1965 was predominantly through hepatobiliary route, with minimal renal clearance. Single i.v. administered acute dose toxicity studies for AT1965 reveal 87.4 mg/kg and 174.8 mg/kg as MTD and toxic doses respectively in rats. Conclusion: The excellent pharmacokinetic profile of AT1965 showing high exposure and enhanced elimination half-life tested across species, in addition to striking antitumor activity coupled with low toxicity in multiple rodent tumor models, provide a compelling rationale for the development of AT1965 as a novel immunotherapeutic agent in the clinic. Citation Format: Aniruddha Sengupta, Mallik Samarla, Manoj Pandey, Arindam Sarkar, Monideepa Roy, Shiladitya Sengupta. Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4918.