Novartis Ag

Karen Vincent

Christoph Heusser

James Rush

Ming Lei

Andreas Loew

Seth Alexander Ettenberg

Li Zhou

Feng Cong

David Jenkins

The present invention relates to silent Fc variants of anti-CD40 antibodies and compositions and methods of use of said antibodies for treating pathological disorders such as autoimmune and inflammatory disorders and/or for preventing or reducing the risk of graft rejection in transplantation.

Method of treating transplant rejection with silent Fc variants of anti-CD40 antibodies

Nucleic acids encoding silent Fc variants of anti-CD40 antibodies

Silent Fc variants of anti-CD40 antibodies

The present disclosure relates to an antibody or antigen binding fragment having at least two receptor binding domains for two different binding sites of LRP6 and compositions and methods of use thereof.

Therapeutic low density lipoprotein-related protein 6 (LRP6) multivalent antibodies

Anti-CD40 antibodies have not been reported to induce hemostatic events in patients, however elevations in pancreatic enzymes in B cell lymphoma patients receiving the anti-CD40 Ab Chir12.12 and the possible risk of pancreatitis precludes the use of this Fc-competent anti-CD40 antibody in chronic autoimmune disease and transplantation for safety reasons. We therefore generated Fc-silent IgG1 anti-CD40 antibodies (mAb1, mAb2 and mAb3) unable to mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) both in vitro and in vivo. mAb1 was able to prolong non-human primate renal allograft survival in combination with sub-therapeutic doses of cyclosporine. In addition, mAb1 was able to completely suppress primary and secondary antibody responses to immunization with a T cell-dependent antigen. Crucially, there was no evidence of hemostatic events or abnormal pancreatic histology in either the transplant or immunization study. Collectively these results suggest mAb1 would be a safe and efficacious therapeutic, and could be used to treat patients suffering from B lymphocyte and antigen presenting cell driven autoimmune disease or undergoing allograft transplant where CD4O-CD154 interactions are involved in contributing to pathology.

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Leymen, France

Karen Vincent