Abstract 1702: Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evaluation of local anti-CTLA-4 application
| العنوان: | Abstract 1702: Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evaluation of local anti-CTLA-4 application |
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| المؤلفون: | Olivia Gardner, Andrea van Elsas, Sarah M. McWhirter, Meredith L. Leong, David Lutje Hulsik, Joost Kreijtz, Jos van de Crommert, Hans van Eenennaam, Astrid Bertens, Imke Lodewijks, Wout Janssen, Maurice Habraken, Maaike Hendriks, Weiwen Deng, Paul Vink, Judith Stammen-Vogelzang |
| المصدر: | Cancer Research. 78:1702-1702 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | CD86, Cancer Research, biology, business.industry, T cell, Context (language use), Pharmacology, Immune checkpoint, Epitope, Toxicology, Immune system, medicine.anatomical_structure, Oncology, medicine, biology.protein, Antibody, business, CD80 |
| الوصف: | 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. |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::3be10bad61f262a7c7ba494176b75c78Test https://doi.org/10.1158/1538-7445.am2018-1702Test |
| رقم الانضمام: | edsair.doi...........3be10bad61f262a7c7ba494176b75c78 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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