Session Information
Date: Sunday, November 12, 2023
Title: (0001–0008) B Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster
Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Glucocorticoids (GCs) are the first-line anti-inflammatory treatment for many autoimmune diseases, but long-term systemic administration of GCs is associated with unwanted side effects, which may be overcome by targeted delivery of GCs via antibodies. The CD40-CD40L costimulatory pathway regulates a wide array of immune cell effector function. The blockage of CD40/CD40L pathway is effective in autoimmune diseases such as Sjögren’s syndrome, but exhibits limited efficacy in severe disease such as systemic lupus erythematosus (SLE). We generated a first-in-class anti-CD40 antibody-glucocorticoid conjugate (anti-CD40 conjugate) that allowed the targeted delivery of GCs to the corresponding immune cells, while blocking CD40/CD40L pathway simultaneously. Here we describe the preclinical characterization of this novel antibody-glucocorticoid conjugate.
Methods: The targeted delivery of GCs was measured by using a CD40-expressing GC reporter cell line. Inhibitory activity of the anti-CD40 conjugate was evaluated in human B and dendritic cells under CD40L stimulation. In addition, Fc-dependent effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), were assessed by co-culturing natural killer (NK) cells or complement proteins with CD40-expressing cell lines. By using human-CD40-transgenic mice, the efficacy of anti-CD40 conjugate was determined in T cell-dependent antibody responses (TDAR) model and skin graft model. Furthermore, a 4-week GLP repeated-dose toxicity study in cynomolgus monkeys was conducted to evaluate the in-vivo safety.
Results: The anti-CD40 conjugate displayed GC receptor activity after being internalized via the membrane CD40 and inhibited CD40L-induced activation of human B or dendritic cells. The anti-CD40 antibody is a humanized antagonist antibody with Fc-silencing mutation to eliminate Fc-dependent effector functions and therefore is unable to mediate ADCC and CDC.We proved that the anti-CD40 conjugate blocked the generation of KLH-specific antibodies in TDAR model. Compared to the anti-CD40 antibody or the combination of anti-CD40 antibody with GC treatment, the anti-CD40 conjugate supported a longer survival of the transplanted skin tissues in the skin graft model. Further, the repeated-dose toxicity study in cynomolgus monkeys showed that the anti-CD40 conjugate was safe and generally well tolerated up to 75 mg/kg. We did not observe adverse effects in cardiovascular, respiratory, and neurobehavioral endpoints. Reduced follicle size and suppression of germinal center in lymph nodes and spleen were seen with immunophenotyping and histology.
Conclusion: Overall, these data demonstrate that the novel anti-CD40-glucocorticoid conjugate has a promising efficacy and safety profile in preclinical models and support the clinical application in diverse autoimmune diseases, including organ transplantation, systemic lupus erythematosus, etc.
To cite this abstract in AMA style:
wang D, Ren W, su l, lin y, liao c. Preclinical Characterization of a Novel anti-CD40 Antagonist Antibody-glucocorticoid Conjugate with Superior Preclinical Efficacy and Favorable Safety Profile [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/preclinical-characterization-of-a-novel-anti-cd40-antagonist-antibody-glucocorticoid-conjugate-with-superior-preclinical-efficacy-and-favorable-safety-profile/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-characterization-of-a-novel-anti-cd40-antagonist-antibody-glucocorticoid-conjugate-with-superior-preclinical-efficacy-and-favorable-safety-profile/