Session Name: Acute Rejection
Session Date & Time: None. Available on demand.
*Purpose: CD40L is a costimulatory receptor for CD40 found on T helper cells. Binding of CD40L on T cells to CD40 on antigen presenting cells induces downstream immune and inflammatory responses. Inhibition of CD40L signaling can abolish inflammation, induce T cell anergy, prevent the progression of autoimmunity, and instill transplant tolerance. AT-1501 is a humanized anti-CD40L antibody lacking Fc effector function with high affinity binding to CD40.
*Methods: A pharmacokinetic study of AT-1501 at 1, 10 and 50 mg/kg was undertaken in rhesus macaques. In addition, we conducted 12 (3, 10, 30, 50 mg/kg) and 26 week (100, 200 mg/kg) toxicology studies with weekly dosing of AT-1501.
*Results: The pharmacokinetic study demonstrated a half-life of 7-9 days at 50 mg/kg. Variability was apparent at lower doses, which was attributed to immunogenicity of AT-1501 in rhesus macaques responding to a human antibody. Plasma concentrations contributing to AUC were affected by the induction of anti-drug antibodies (ADA) and occurred markedly at 1 mg/kg, to an intermediate extent at 10 mg/kg, and was absent at 50 mg/kg. At 10 mg/kg, half of the animals elicited ADA responses, which were non-neutralizing and did not impact AT-1501 binding to CD40L at either 3 or 10 mg/kg. ADA responses were not observed above 10 mg/kg. All animals in the 100 mg/kg dose group completed the study, remained healthy and AT-1501 concentrations in plasma were as predicted. Animals in the 200 mg/kg group survived through 16 weeks without evidence of gross pathology. Four 200 mg/kg animals showed signs of toxicity and were euthanized at 17, 18, 25 and 26 weeks. Data were suggestive of a Type III hypersensitivity infusion reaction (IR) resulting in immune-complex (IC) formation, impacting multiple organs but primarily resulting in kidney pathology and dysfunction. Clinical chemistry and histopathology confirmed extravascular localization of AT-1501, NHP IgG1, IgM, Albumin, and C3. ICs were comprised of IgM, demonstrating that AT-1501 blocked IgM to IgG class switching.
*Conclusions: These data demonstrate functional activity of AT-1501 in vivo. Thus, weekly doses of AT-1501 at 10 mg/kg or higher are considered therapeutic dosing, leading to levels that inhibit antigen presentation and pro-inflammatory lymphocyte signaling. The results for the 200 mg/kg group support a conclusion that the toxicity was due to the high concentration of circulating AT-1501, leading to IC formation and not due to the mechanism of action of the drug.
To cite this abstract in AMA style:Perrin S, Gill A, Gill C, Vieira F, Thompson K. Pharmacokinetic and Toxicity Studies of an Anti CD40L Antibody, At-1501 in Rhesus Macaques [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/pharmacokinetic-and-toxicity-studies-of-an-anti-cd40l-antibody-at-1501-in-rhesus-macaques/. Accessed July 24, 2021.
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