Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody
| Autor: | James S. Rush, Christoph Heusser, Dorothee Müller-Ristig, Peter Ulrich, Christian Bruns, Pascal Espie, Gautier Robert, Doris Weider, Patrick Schmutz, Serge Côté, Max Warncke, Jacinda Ristov, Frank Kolbinger, Francisco Cordoba-Castro, Thierry Flandre, Denise Sickert, Barbara Greutmann, Martin A. Schneider, Mirela Dimitrova |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.drug_class T-Lymphocytes CD40 Ligand 030230 surgery In Vitro Techniques medicine.disease_cause Monoclonal antibody 03 medical and health sciences 0302 clinical medicine Immune system In vivo medicine Immunology and Allergy Animals Humans Pharmacology (medical) Tissue Distribution CD40 Antigens Antigen-presenting cell Transplantation Mutation CD40 biology business.industry Antibodies Monoclonal In vitro Macaca fascicularis 030104 developmental biology Immunology biology.protein Antibody business |
| Zdroj: | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 18(12) |
| ISSN: | 1600-6143 |
| Popis: | The CD40-CD154 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 CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 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 CFZ533 and CD40 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. |
| Databáze: | OpenAIRE |
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