The immune checkpoint CTLA-4 can be targeted with antibodies that are applied as single agent therapy or in combination with other therapies including surgery, radiation and chemotherapy. Anti-CTLA-4 antibodies may also augment other immunotherapies. Indeed, in syngeneic mouse tumor models anti-CTLA-4 strongly enhanced anti-tumor efficacy of live, attenuated double-deleted Listeria monocytogenes (LADD) and of the STING pathway activator ADU-S100. Anti-CTLA-4 therapy has shown clinical activity and durable responses in advanced cancers, but is also associated with severe immune-related adverse events (irAEs), although manageable and reversible. Local anti-CTLA4 application could limit the induction of irAEs while retaining its capacity to induce and enhance tumor-specific T cell responses.
Here we present the results from the preclinical development of ADU-1604, a novel hIgG1 anti-CTLA-4 antibody. ADU-1604 binds a unique epitope on human CTLA-4 and was extensively characterized in vitro demonstrating potent CTLA-4 binding and blockade of CD80 and CD86 and its capability to enhance human T cell responses. As the antibody cross-recognizes CTLA-4 of cynomolgus monkeys this species was selected for the preclinical studies. Male animals received a single intravenous dose of the antibody to assess its pharmacokinetics and pharmacodynamics. ADU-1604 was well tolerated and showed an acceptable half-life. The antibody also enhanced the T cell-dependent antibody response in hepatitis B surface antigen immunized animals. After the single dose PK study a GLP 4-week repeat-dose toxicity study was conducted in cynomolgus monkeys administered 5 doses of ADU-1604 intravenously once a week followed by an 8-week recovery period. In general, ADU-1604 was well tolerated at up to 30 mg/kg/dose. Histopathology data is being processed and recovery data is pending.
Proof of concept for the local administration of anti-CTLA-4 antibodies was conducted in syngeneic mouse models with the mouse CTLA-4 antibody 9D9 and in NSCLC humanized PDX models using ADU-1604 in the context of CD45+ human immune cells. These models demonstrated anti-tumor activity of systemically applied ADU-1604, comparable to a reference anti-CTLA-4 antibody. Intratumoral application of ADU-1604 in these models also induced tumor growth inhibition
In conclusion, the preclinical development package warrants clinical investigation of ADU-1604 as monotherapy and for future combinations with other Aduro proprietary platforms including STING agonists and (p)LADD. Currently ADU-1604 is progressing through regulatory filing in preparation of clinical development.
Citation Format: Maaike Hendriks, Joost Kreijtz, Paul Vink, David Lutje Hulsik, Imke Lodewijks, Astrid Bertens, Jos van de Crommert, Maurice Habraken, Wout Janssen, Judith Stammen-Vogelzang, Olivia Gardner, Weiwen Deng, Meredith Leong, Sarah McWhirter, Hans van Eenennaam, Andrea van Elsas. Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evaluation of local anti-CTLA-4 application [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 1702.