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Chronic administration of belatacept, a T-cell costimulatory signal blocker, in cynomolgus monkeys.
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- Author(s): Haggerty HG;Haggerty HG; Proctor SJ
- Source:
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2012 May; Vol. 127 (1), pp. 159-68. Date of Electronic Publication: 2012 Feb 13.
- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't
- Language:
English
- Additional Information
- Source:
Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE
- Publication Information:
Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-
- Subject Terms:
- Abstract:
The toxicokinetics and toxicity profile of belatacept (LEA29Y), which blocks the CD28 costimulation pathway to prevent T-cell activation, were evaluated in cynomolgus monkeys. In the current study, 30 monkeys (five monkeys per sex per group) received an intravenous dose of belatacept (10, 22, or 50 mg/kg) once weekly for 6 months. An additional five monkeys per sex received saline intravenously and served as controls. Systemic exposure to belatacept was dose proportional and similar for both sexes. Multiple dosing resulted in moderate belatacept accumulation (1.6- to 1.9-fold). Belatacept was clinically well tolerated in monkeys, with no drug-related laboratory parameter changes or target organ toxicity observed, including a lack of nephrotoxicity. Drug-related changes, which were reversible and related to the pharmacology, included dose-dependent minimal/mild reduction in the size and number of lymphoid germinal centers of the spleen and lymph nodes and minimal reductions in serum IgG levels. No antibodies specific for belatacept were detected during the treatment period. There were no changes in peripheral blood or splenic lymphocyte subpopulations or indications of autoimmune-like inflammation, infection, or malignancy, including preneoplastic changes. Functional recovery of the immune system was noted at all doses by a robust antibody response to keyhole limpet hemocyanin following immunization 2 months after the last belatacept dose was administered. Thus, belatacept was well tolerated in monkeys treated for 6 months at weekly doses up to 50 mg/kg, which represented a 20-fold increase above exposures achieved by the approved maintenance dose in kidney transplant recipients. These findings support the belatacept safety profile and demonstrate that belatacept does not result in adverse renal effects.
- Accession Number:
0 (CD28 Antigens)
0 (Immunoconjugates)
0 (Immunoglobulins)
0 (Immunosuppressive Agents)
7D0YB67S97 (Abatacept)
9013-72-3 (Hemocyanins)
FV4Y0JO2CX (keyhole-limpet hemocyanin)
- Publication Date:
Date Created: 20120215 Date Completed: 20120808 Latest Revision: 20171116
- Publication Date:
20240829
- Accession Number:
10.1093/toxsci/kfs081
- Accession Number:
22331490
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