ABSTRACT
Anti-factor VIII (FVIII) antibody development poses a significant challenge in hemophilia A (HA) patients receiving FVIII protein replacement therapy. There is an urgent need for novel therapeutic strategies to inhibit the production of anti-FVIII inhibitory antibodies (inhibitors) in HA. This study aimed to investigate a combination monoclonal antibody (mAb) therapy targeting CXCL13 and CD20 on the development of anti-FVIII antibodies in a HA murine model, along with the underlying mechanisms involved. Specifically, mAbs targeting mouse CD20 (18B12) with an IgG2a backbone and mouse CXCL13 (2C4) with an IgG1 backbone were synthesized. HA mice with FVIII inhibitors were established, and the results revealed that the combination therapy of anti-mCD20 with α-mCXCL13 significantly suppressed anti-FVIII antibody development and induced FVIII tolerance. Furthermore, this combination therapy led to a marked reduction of peripheral and splenic follicular helper T cells and an enhancement of regulatory T cell induction, along with sustained depletion of bone marrow and splenic plasma cells in HA mice with preexisting FVIII immunity. Thus, the concurrence of blockage of CD20 and neutralization of CXCL13 hold promise as a therapeutic strategy for HA patients with inhibitors.
Subject(s)
Antibodies, Monoclonal , Chemokine CXCL13 , Factor VIII , Hemophilia A , Animals , Hemophilia A/drug therapy , Hemophilia A/immunology , Factor VIII/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/immunology , Mice , Chemokine CXCL13/immunology , Chemokine CXCL13/metabolism , Humans , Antigens, CD20/immunology , Disease Models, Animal , Mice, Inbred C57BL , MaleABSTRACT
Starting from aromatic ortho-dialdehydes, we devised a homo-elongation protocol that combines a Wittig olefination and subsequent intramolecular Knoevenagel condensation to produce acene diesters and dinitriles.