Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
An Assessment of theThromboembolic Potential of CDP7657, a Monovalent Fab' PEG Anti-CD40L Antibody, in Rhesus Macaques.
Wakefield2, Ian, Harari2, Olivier, Hutto1, David, Burkly1, Linda, Ferrant1, Janine, Taylor1, Fred, Robinson2, Martyn
CDP7657 is a novel monovalent Fab' PEG anti-CD40L antibody being developed for the treatment of Systemic Lupus Erythematosus (SLE) and currently in a phase I clinical study. Previously, an anti-human CD40L intact IgG1 mAb, hu5c8 (Antova), has been associated with thromboembolic events in the clinic and subsequent investigations of hu5c8 in Rhesus macaques revealed extensive pulmonary thrombovasculopathy with intimal hyperplasia (IH). CDP7657 and other Fc function-deficient anti-CD40L antibody constructs were evaluated in Rhesus monkeys for their potential to induce thrombosis and vascular lesions as part of a non-clinical safety evaluation program.
Three studies were conducted in Rhesus monkeys. In the initial study, the hu5c8 mAb was administered i.v. weekly at 50mg/kg/week for 8 weeks. A second 8-week study investigated two PEGylated antibody fragments (the monovalent Fab' PEG CDP7657 and a bivalent di-Fab' PEG format using the same variable region) and two intact mAbs (hu5c8, and the Fc function-deficient aglycosyl hu5c8). These agents were administered i.v. weekly (50mg/kg) and compared with saline-injected control animals. In the third study, CDP7657 was administered i.v. weekly at doses of 20, 50, or 200 mg/kg (8/sex/group) for 12 weeks, while control animals (16/sex) received saline. Reversibility groups were assessed for 4 or 6 months. In all studies, there was extensive histopathology evaluation of the lungs (29 sections/animal).
In the first study, hu5c8 produced widespread severe pulmonary vasculopathy in animals, consisting of intravascular thrombosis and IH. In the second study, hu5c8 also produced pulmonary intravascular thrombosis or IH in the lungs of 5 of 8 animals. Secondary changes were observed including recanalization of arterial thrombi, intra-alveolar hemorrhage, perivascular inflammation and fibrosis and coagulative necrosis of the lung parenchyma. By contrast, CDP7657 and other anti-CD40L antibody constructs lacking a functional Fc region were associated with an incidence of pulmonary changes comparable to that found in control animals. In the third study, CDP7657 showed no evidence of compound-related pulmonary or extra-pulmonary thrombovasculopathy after the treatment or reversibility periods and no other findings of toxicological significance at any dose level.
The pulmonary thrombovasculopathy observed with the hu5c8 mAb in Rhesus macaques is associated with the presence of a functional Fc region, and is not caused by CD40L blockade alone, or on the valency of the blockade, as seen by the absence of these pulmonary effects with the other antibody constructs. These data support the clinical testing of CDP7657 in humans for treatment of SLE and other immune-mediated diseases.
To cite this abstract, please use the following information:
Wakefield, Ian, Harari, Olivier, Hutto, David, Burkly, Linda, Ferrant, Janine, Taylor, Fred, et al; An Assessment of theThromboembolic Potential of CDP7657, a Monovalent Fab' PEG Anti-CD40L Antibody, in Rhesus Macaques. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1243