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Characterization of the in vitro and in vivo properties of CFZ 533, a blocking and non‐depleting anti‐ CD 40 monoclonal antibody
Author(s) -
Ristov Jacinda,
Espie Pascal,
Ulrich Peter,
Sickert Denise,
Flandre Thierry,
Dimitrova Mirela,
MüllerRistig Dorothee,
Weider Doris,
Robert Gautier,
Schmutz Patrick,
Greutmann Barbara,
CordobaCastro Francisco,
Schneider Martin A.,
Warncke Max,
Kolbinger Frank,
Cote Serge,
Heusser Christoph,
Bruns Christian,
Rush James S.
Publication year - 2018
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14872
Subject(s) - cd154 , cd40 , monoclonal antibody , immunology , immune system , germinal center , antibody , in vivo , medicine , blocking antibody , b cell , transplantation , in vitro , microbiology and biotechnology , biology , cytotoxic t cell , biochemistry
The CD 40‐ CD 154 costimulatory pathway is essential for T cell–dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ 533, a fully human, pathway blocking anti‐ CD 40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ‐dependent effector functions. CFZ 533 inhibited CD 154‐induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ 533 was unable to mediate depletion of human CD 40 expressing B cells. In vivo, CFZ 533 blocked primary and recall T cell‐dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ 533 and CD 40 pathway‐relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.