Humanized anti-CD19 antibodies and their use in treatment of oncology, transplantation and autoimmune disease
Inventors
Damschroder, Melissa • Kiener, Peter • Wu, Herren • DALLACQUA WILLIAM, null • Dall'Acqua, William • Herbst, Ronald • Coyle, Anthony
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9896505-B2
Publication Date
2018-02-20
Expiration Date
Abstract
The present invention provides chimeric and humanized versions of anti-CD19 mouse monoclonal antibodies. The invention further relates to pharmaceutical compositions, immunotherapeutic compositions, and methods using therapeutic antibodies that bind to the human CD19 antigen and that may mediate ADCC, CDC, and/or apoptosis for the treatment of B cell diseases and disorders, such as, but not limited to, B cell malignancies, for the treatment and prevention of autoimmune disease, and for the treatment and prevention of graft-versus-host disease (GVHD), humoral rejection, and post-transplantation lymphoproliferative disorder in human transplant recipients.
Core Innovation
The invention provides a method of treating a B cell disease or disorder in a human by administering a therapeutically-effective amount of an antibody that binds a human CD19 antigen. The antibody is a chimeric, humanized or human monoclonal antibody or fragment thereof comprising a VH with amino acid sequence SEQ ID NO.: 106 and a VL with amino acid sequence SEQ ID NO.: 111, and having complex N-glycoside-linked sugar chains bound to the Fc region in which fucose is not bound to N-acetylglucosamine in the reducing end of the sugar chain.
The disclosed content links the CD19-binding antibody with B-cell depletion across multiple B-cell subsets in vivo, including circulating, blood, splenic, marginal zone, follicular, peritoneal, and bone marrow B cells. It also describes depletion of progenitor, precursor, immature, mature, antigen stimulated, and plasma cells, together with mature, splenic follicular and marginal zone, and bone marrow total B, pro-B, pre-B, and peritoneal cavity B cells.
Beyond depletion, the patent content characterizes functional dependence considerations for anti-CD19 depletion and persistence, including effects associated with CD19 density, FcγR/ADCC dependence, durability/time course, and CD19 surface persistence and loss kinetics. It also states B-cell proliferation inhibition via CD19 phosphorylation and Erk1/2 modulation, suppression of proliferation induced by anti-IgM/CD40 and anti-IgM/CpG, effects on humoral immunity/autoimmunity, and in vivo tumor growth reduction in an in vivo lymphoma model.
Claims Coverage
The independent claims cover treatment of a human B cell disease or disorder using a defined CD19-binding antibody, together with depletion of selected anatomical and compartmental B-cell populations and selected progenitor, precursor, mature, activated, and plasma B-cell populations.
CD19-targeting antibody treatment for B cell diseases
Administering to a human in need thereof a therapeutically-effective amount of an antibody that is a chimeric, humanized or human monoclonal antibody or fragment thereof, comprising a VH comprising the amino acid sequence SEQ ID NO.: 106 and a VL comprising the amino acid sequence SEQ ID NO.: 111, having complex N-glycoside-linked sugar chains bound to the Fc region in which fucose is not bound to N-acetylglucosamine in the reducing end in the sugar chain, and binding a human CD19 antigen, wherein the disease or disorder is selected from B cell malignancy, autoimmune disease, autoimmune disorder, humoral rejection in a human transplant patient, graft-versus-host disease (GVHD), and post-transplantation lymphoproliferative disorder in human transplant recipient.
Depleting selected anatomical and compartmental B cell populations
Depleting B cells selected from circulating B cells, blood B cells, splenic B cells, marginal zone B cells, follicular B cells, peritoneal B cells, and/or bone marrow B cells.
Depleting selected progenitor/precursor, mature/activated, and plasma B cell populations
Depleting B cells selected from progenitor B cells, early pro-B cells, late pro-B cells, large-pre-B cells, small pre-B cells, immature B cells, mature B cells, antigen stimulated B cells, and/or plasma cells.
Across the independent claims, the inventive concept is treatment of human B cell diseases using a defined CD19-binding antibody with specified VH/VL sequence constraints and an Fc glycosylation pattern, together with depletion of selected B-cell subsets including compartment-specific populations and progenitor-to-plasma cell categories.
Stated Advantages
Inhibits B-cell proliferation.
Provides B-cell depletion.
Provides effector mechanisms characterized as ADCC, CDC, and apoptosis.
Enhanced ADCC activity.
Wider B cell targeting.
Reduced need for severe regimens.
Documented Applications
Treatment of a B cell disease or disorder in a human including B cell malignancy, autoimmune disease, autoimmune disorder, humoral rejection in a human transplant patient, graft-versus-host disease (GVHD), and post-transplantation lymphoproliferative disorder in a human transplant recipient.
Treatment of B cell malignancy.
Treatment of autoimmune disease or autoimmune disorder.
Treatment of humoral rejection in a human transplant patient.
Treatment of graft-versus-host disease (GVHD) in a human transplant recipient.
Treatment of post-transplantation lymphoproliferative disorder in a human transplant recipient.
Interested in licensing this patent?