Authors
Maaike Hendriks1, Joost Kreijtz1, Paul Vink1, David Lutje Hulsik1, Imke Lodewijks1, Astrid Bertens1, Jos van de Crommert1, Maurice Habraken1, Wout Janssen1, Judith Stammen-Vogelzang1, Lilian Driessen1, Weiwen Deng2, Meredith Leong2, Victor Lira2, Sarah McWhirter2, Hans van Eenennaam1, Andrea van Elsas1
Organizations
- Aduro Biotech Europe, Oss, The Netherlands
- Aduro Biotech, Berkeley, CA, USA
Abstract
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.
CovalX Technology Used (Click each option to learn more)
Outcomes
The unique epitope on Cytotoxic T-lymphocyte-associated protein 4 (hCTLA-4) that humanized hIgG1 CTLA-4 antagonist (ADU-1604) binds to was found using mass spectrometry. Specifically, by deuterated chemical crosslinking, enzymatic digestion and peptide mass fingerprinting. The goal of the research was to evaluate the safety of ADU-1604 and it’s uses for metastatic melanoma in adult patients in comparison to an already approved treatment known as ipilimumab. Ipilimumab was subjected to the same procedures and it was found that the epitope residues overlap with those identified in the X-ray structure.
Source
Poster #1702, 2018