Decreased immune response in monkeys administered a human T-effector cell agonist (OX40) antibody
| Autor: | Frank J. Simutis, Joshua T. Gamse, Michael J. Graziano, Helen G. Haggerty, Rashade Haynes, Wendy J. Freebern, Mary Pazian, James Crona, Roderick T. Bunch |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist Male medicine.drug_class medicine.medical_treatment T-Lymphocytes Pharmacology Toxicology 03 medical and health sciences 0302 clinical medicine Immune system medicine Animals Humans Cytotoxicity Receptor biology business.industry Immunity Antibodies Monoclonal Receptors OX40 Macaca fascicularis 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Pharmacodynamics Toxicity biology.protein Female Immunotherapy Antibody business Follow-Up Studies |
| Zdroj: | Toxicology and applied pharmacology. 409 |
| ISSN: | 1096-0333 |
| Popis: | The OX40 receptor plays a crucial co-stimulatory role in T effector cell survival, expansion, cytokine production, and cytotoxicity to tumor cells; therefore, OX40 agonists are being evaluated as anti-cancer immunotherapies, especially in combination with checkpoint inhibitors. To support clinical development of BMS-986178 (an OX40 agonist antibody), two repeat-dose toxicity studies were conducted in cynomolgus monkeys. In the first study, BMS-986178 was administered intravenously (IV) once weekly for one month at doses from 30 to 120 mg/kg. BMS-986178 was well tolerated; surprisingly, immune function was suppressed rather than increased based on pharmacodynamic (PD) and flow cytometry readouts (e.g. T-cell dependent antibody response [TDAR]). To determine whether immune suppression was due to a bi-phasic response, a follow-up study was conducted at lower doses (1 and 10 mg/kg). Although receptor engagement was confirmed, immune function was still suppressed at both doses. In addition, treatment-emergent anti-drug antibodies (ADAs) at 1 mg/kg resulted in hypersensitivity reactions and reduced BMS-986178 exposure after repeated dosing, which precluded a full PD assessment at this dose. In conclusion, BMS-986178 was clinically well-tolerated by monkeys at weekly IV doses from 10 to 120 mg/kg (AUC[0–168] ≤ 712,000 μg●h/mL). However, despite target engagement, PD assays and other immune endpoints demonstrated immune suppression, not stimulation. Due to the inverted immune response at higher doses and the onset of ADAs, additional repeat-dose toxicity studies of BMS-986178 in monkeys (that would typically be required to support Phase 3 clinical trials and registration) would not add value for human safety assessment. |
| Databáze: | OpenAIRE |
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