Humanized anti-CD19 antibodies
Inventors
Damschroder, Melissa • Kiener, Peter • Wu, Herren • Dall'Acqua, William • Herbst, Ronald • Coyle, Anthony
Assignees
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Publication Number
US-8883992-B2
Publication Date
2014-11-11
Expiration Date
Abstract
Isolated nucleic acids encoding anti-CD19 mouse monoclonal antibodies are described herein. Also described are expression vectors, host cells and a method of producing anti-CD19 antibodies.
Core Innovation
The disclosed subject matter relates to humanized and chimeric anti-CD19 antibodies, including engineered HB12A and HB12B derivatives, that bind human CD19 antigen. The antibodies inhibit B-cell proliferation under IgM/CpG and IgM/CD40 stimulation and mediate antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis.
The invention further describes Fc-variant antibodies with altered Fc–ligand affinities, emphasizing enhanced binding to FcγRIIB alongside interactions with FcγRIIIA and FcRn. These Fc engineering effects, including afucosylation and ADCC-ablated and enhanced variants, are linked to potency differences and B-cell depletion efficacy.
The technical framework includes polynucleotides, expression vectors, and host cells for antibody production. The antibodies are typically presented as humanized or chimeric IgG1 or IgG3 isotypes, and the described constructs facilitate anti-CD19 immunotherapy, diagnostic uses, and monitoring in B-cell malignancies, autoimmune diseases, and transplant-related complications.
Claims Coverage
The claims include three main inventive feature sets directed to isolated nucleic acids and expression vectors encoding CD19-binding polypeptides.
Isolated nucleic acid encoding polypeptide comprising SEQ ID NO: 106
An isolated nucleic acid encoding a polypeptide comprising an amino acid sequence comprising SEQ ID NO: 106.
Isolated nucleic acid encoding polypeptide comprising SEQ ID NO: 111
An isolated nucleic acid encoding a polypeptide comprising an amino acid sequence comprising SEQ ID NO: 111.
Expression vector encoding SEQ ID NO: 106 and 111 antibody binding CD19
An expression vector comprising an isolated nucleic acid encoding an antibody comprising the amino acid sequence of SEQ ID NO: 106 and 111, wherein the antibody binds a CD19 antigen.
Overall, the claims cover isolated nucleic acids defined by SEQ ID NO: 106 and SEQ ID NO: 111, and expression vectors encoding CD19-binding antibodies incorporating both sequences, with dependent coverage extending to host cells and production methods.
Stated Advantages
Inhibition of in vitro stimulated B-cell proliferation under IgM/CpG and IgM/CD40 stimulation.
Enhanced binding to FcγRIIB using Fc-variant antibodies with altered Fc–ligand affinities.
The antibodies can mediate ADCC, CDC, and apoptosis.
Documented differences in potency and B-cell depletion efficacy across Fc-engineered embodiments.
Ability to achieve in vivo B-cell depletion and tumor growth inhibition in documented models.
Provides in vivo and in vitro evidence for anti-CD19 antibody-mediated B cell depletion and function.
Shows in vivo lymphoma tumor growth inhibition dependent on ADCC.
Supports enhanced ADCC for affinity-matured antibodies, including afucosylated forms.
Reports in vivo B cell depletion with dose-dependent recovery.
Documented Applications
Treating B-cell malignancies through the depletion of circulating B cells and/or immunoglobulin.
Treating autoimmune diseases utilizing anti-CD19 antibodies to deplete circulating B cells.
Treating transplant-related complications, including GVHD, graft rejection, and humoral rejection.
Patient selection and treatment of autoimmune diseases (RA, SLE, ITP, pemphigus/pemphigoid, autoimmune diabetes (type 1A), and systemic sclerosis/scleroderma) with anti-CD19 antibody compositions.
Determining CD19 antigen density in samples using flow cytometry, Scatchard/radiolabeling, and in vivo imaging including PET/SPECT with radiolabeled anti-CD19.
Anti-CD19 immunotherapy involving B-cell depletion and monitoring, including immune reconstitution and tumor burden monitoring.
Diagnostic/prognostic or monitoring uses of anti-CD19 antibodies conjugated to detectable agents or radiolabels like indium.
In vivo evaluation for depletion of bone marrow immature B cells (CD93+), mature B cells (CD93 low/−), and peritoneal IgM+ B cells.
In vivo lymphoma tumor xenograft growth inhibition using 3649 humanized anti-CD19.
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