Engineering of a novel anti-CD40L domain antibody for treatment of autoimmune diseases
| Autor: | Steven Grant, Suzanne J. Suchard, Robert P. Rehfuss, Steven G. Nadler, Kathleen M. Gillooly, Anish Suri, Robert Kuhn, Ruth Brosius, Yifan Zhang, Rathna Ravishankar, Kathy A Mink, Aaron P. Yamniuk, Sandra Rex-Rabe, Jenny Xie, Philip Drew, Luisa Salter-Cid, Kimberly S Waggie, James William Bryson, Olga Ignatovich, Lin Cheng, Laura Price, Xiadi Zhou, Yongmi An, James K. Tamura, Virna Borowski, Xiaoxia Yang, Bozena Abramczyk, Vojkan Susulic |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.drug_class
T cell Immunology CD40 Ligand chemical and pharmacologic phenomena Monoclonal antibody Lymphocyte Activation Transfection Autoimmune Diseases Mice Thromboembolism medicine Immunology and Allergy Animals Humans Platelet activation Receptor biology Effector Chemistry Receptors IgG Antibodies Monoclonal hemic and immune systems Dendritic cell Single-Domain Antibodies Surface Plasmon Resonance Platelet Activation Transplantation Disease Models Animal medicine.anatomical_structure HEK293 Cells Cancer research biology.protein Antibody |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 192(9) |
| ISSN: | 1550-6606 |
| Popis: | CD40–CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects in patients with autoimmune diseases; however, incidents of thromboembolism (TE) precluded further development of these molecules. In this study, we examined the role of the Fc domain interaction with FcγRs in modulating platelet activation and potential for TE. Our results show that the interaction of the 5c8 wild-type IgG1 Fc domain with FcγRs is responsible for platelet activation, as measured by induction of PAC-1 and CD62P. A version of 5c8 with a mutated IgG1 tail was identified that showed minimal FcγR binding and platelet activation while maintaining full binding to CD40L. To address whether Fc effector function is required for immunosuppression, a potent Ab fragment, termed a “domain Ab” (dAb), against murine CD40L was identified and fused to a murine IgG1 Fc domain containing a D265A mutation that lacks Fc effector function. In vitro, this dAb–Fc demonstrated comparable potency to the benchmark mAb MR-1 in inhibiting B cell and dendritic cell activation. Furthermore, the anti-CD40L dAb–Fc exhibited a notable efficacy comparable to MR-1 in various preclinical models, such as keyhole limpet hemocyanin–induced Ab responses, alloantigen-induced T cell proliferation, “heart-to-ear” transplantation, and NZB × NZW F1 spontaneous lupus. Thus, our data show that immunosuppression and TE can be uncoupled and that a CD40L dAb with an inert Fc tail is expected to be efficacious for treating autoimmune diseases, with reduced risk for TE. |
| Databáze: | OpenAIRE |
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