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.
CDP7657, a Monovalent Fab PEG Anti-CD40L Antibody, Inhibits Immune Responses in Both HuSCID Mice and Non-Human Primates.
Wakefield2, Ian, Peters2, Christopher, Burkly1, Linda, Garber1, Ellen, Ferrant1, Janine, Taylor1, Fred, Su1, Lihe
CDP7657 is a novel monovalent Fab' PEG anti-human CD40L antibody being developed for the treatment of Systemic Lupus Erythematosus (SLE) and is currently in a phase I clinical study. CD40L is a key regulator of T-cell dependent activation of accessory cells, particularly B cells and other antigen presenting cells. These studies were designed to evaluate the capacity of CDP7657, and other anti-CD40L antibody contructs, to block the humoral immune response to tetanus toxoid (TT) in both HuSCID mice and Cynomolgus macaques.
For the HuSCID study, CB17 SCID mice were dosed s.c. with CDP7657, hu5c8 (a humanized anti-human CD40L intact IgG1 mAb) or an aglycosyl (Fc function-deficient) form of hu5c8. Human peripheral blood mononuclear cells (PBMC) and TT were then injected into the mice. The number of antibody forming cells generating human anti-TT IgG was determined on day 14 by ELISpot.
For the Cynomolgus macaque studies, different anti-CD40L mAb constructs were given as a single i.v. dose. In addition to CDP7657, hu5c8 and aglycosyl hu5c8, the variable regions of CDP7657 in bivalent di-Fab' PEG and intact aglycosyl (human IgG4) mAb formats were also tested. The effect of these entities on the primary and secondary anti-TT responses was monitored.
In the HuSCID model, CDP7657 demonstrated a dose-dependent inhibition of the anti-TT antibody response with equivalent efficacy to that of aglycosyl hu5c8. Although all three entities were able to completely block the anti-TT immune response, the IgG1 version of hu5c8 was the most potent in this model system.
In the Cynomolgus macaque, all of the anti-CD40L molecules were capable of inhibiting the primary IgM and IgG anti-TT antibody responses, with a comparable degree of efficacy observed between CDP7657, the diFab' PEG and the aglycosyl IgG antibody constructs. CDP7657 demonstrated a dose related effect on both primary and secondary (after re-challenge with TT) immune responses and also was able to effectively suppress secondary responses.
CDP7657 dose-dependently inhibited the immune response to TT in both HuSCID mice and Cynomolgus macaques. The inactive Fc formats tested had decreased efficacy in both models relative to hu5c8 which may reflect the potential depleting capacity of this active isotype. Demonstration of the effective inhibition of CD40L-dependent immune responses by CDP7657 supports the therapeutic potential of this molecule for the treatment of human immune-mediated diseases such as SLE.
To cite this abstract, please use the following information:
Wakefield, Ian, Peters, Christopher, Burkly, Linda, Garber, Ellen, Ferrant, Janine, Taylor, Fred, et al; CDP7657, a Monovalent Fab PEG Anti-CD40L Antibody, Inhibits Immune Responses in Both HuSCID Mice and Non-Human Primates. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1245