Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
CD40-CD40L interactions play a central role in T-B cell costimulation. Targeting this pathway has generated great interest; however early attempts to target CD40L failed mainly due to thrombotic complications observed in the clinic. In addition, developing antagonistic CD40 antibodies with suitable potency, favorable PK and no agonistic activity has proven to be challenging. BI 655064 is an anti-human CD40 mAb being developed for the treatment of autoimmune disorders. BI 655064 is engineered as a human IgG1 molecule with a mutated Fc region to abrogate effector function. Here we describe the preclinical characterization of BI 655064.
Methods:
Binding of BI 655064 to CD40 expressed on primary B cells was measured by flow cytometry. The ability of BI 655064 to block CD40L-induced B cell proliferation in vitro was measured by tritium uptake. A subcutaneous PK/PD study in the cynomolgus monkey was performed to establish correlations between BI 655064 exposure, target coverage using a receptor occupancy assay and pharmacodynamic effects using an ex vivo CD54-induction assay. In vivo blockade of B cell function was also tested in a human-peripheral blood lymphocyte (huPBL) induced SCID mouse model of graft-versus-host disease (GvHD) and in cynomolgus monkeys immunized with keyhole limpet hemocyanin (KLH).
Results:
BI 655064 binds human CD40 on B cells present in whole blood with an EC90 value of 6.85 nM ± 0.74. Blockade of CD40L-induced B cell proliferation was observed at an average IC50 of 0.4 nM. In the PK/PD study, cynomolgus monkeys dosed with greater than 1 mg/kg of BI 655064 exhibited complete blockade of ex vivo CD54 upregulation corresponding to full CD40 target coverage on B cells. In vivo, BI 655064 demonstrated clear effects on B cell function in the GvHD model where both human IgM and IgG responses were abrogated. As part of a repeat dose tolerability study, BI 655064 given to cynomolgus monkeys prior to immunization with KLH resulted in inhibition of KLH-specific IgM and IgG antibody responses. At doses of 5 mg/kg and above, germinal center size was decreased microscopically in Peyer’s patches, lymph nodes, spleens and tonsils in treated monkeys.
Conclusion:
BI 655064 is a humanized antagonistic anti-CD40 mAb which is to be tested in human clinical trials for autoimmune disorders to establish safety and efficacy. BI 655064 demonstrated relevant pharmacologic in vitro and in vivo activity, blocking CD40-related functions at clinical dosing levels of > 1 mg/kg in animal models.
Disclosure:
K. Ralph,
Boehringer Ingelheim,
3;
A. Nicoletti,
Boehringer Ingelheim,
3;
E. Musvasva,
Boehringer Ingelheim,
3;
S. Cannan,
Boehringer Ingelheim,
3;
S. VanTongeren,
Boehringer Ingelheim,
3;
D. Blanset,
Boehringer Ingelheim,
3;
S. Brodeur,
Boehringer Ingelheim,
3;
J. Ahlberg,
Boehringer Ingelheim,
3;
H. Li,
Boehringer Ingelheim,
3;
S. Fogal,
Boehringer Ingelheim,
3;
S. Desai,
Boehringer Ingelheim,
3;
K. O’Shea,
Boehringer Ingelheim,
3;
R. Kroe-Barrett,
Boehringer Ingelheim,
3;
G. Nabozny,
Boehringer Ingelheim,
3;
H. Wu,
Boehringer Ingelheim,
3;
G. Hansen,
Boehringer Ingelheim,
3;
K. Canada,
Boehringer Ingelheim,
3;
S. Singh,
Boehringer Ingelheim,
3;
M. Ramanujam,
Boehringer Ingelheim,
3;
C. Grimaldi,
Boehringer Ingelheim,
3.
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