Monoclonal immunoglobulin for use in diagnosis, prevention and treatment of cell proliferative, graft vs host and immunological disorders
Inventors
Damschroder, Melissa • Kiener, Peter • Wu, Herren • Dall'Acqua, William • Herbst, Ronald • Coyle, Anthony
Assignees
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Publication Number
US-8323653-B2
Publication Date
2012-12-04
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 relates to isolated purified chimeric, humanized or human monoclonal antibodies or fragments thereof that bind a human CD19 antigen. The disclosed antibodies comprise a VH comprising the amino acid sequence of SEQ ID NO.:106 and a VL comprising the amino acid sequence of SEQ ID NO.:111. The document describes humanized/chimeric anti-CD19 antibodies derived from HB12A and HB12B and provides binding to human CD19 with engagement of immune effector functions.
The antibodies mediate immune effector functions including ADCC, CDC and/or apoptosis, and inhibit anti-IgM/CpG-stimulated B-cell proliferation. The document further links in vivo depletion and recovery to CD19 density and FcγR dependence, including FcγRI, FcγRII and FcγRIII, and reports binding kinetics/affinity, B-cell depletion capability, and downstream effects on humoral immunity.
The document also describes Fc-related structural and functional attributes, including 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, together with Fc variant affinity constraints for FcγRIIIA and FcγRIIB. It further describes polynucleotides and vectors for expression, supporting generation of chimeric, humanized and/or human anti-CD19 antibodies with defined variable-region sequences and associated antibody properties.
Claims Coverage
The independent claim covers an isolated purified chimeric, humanized or human monoclonal antibody or fragment thereof that binds human CD19. The dependent claims add 6 inventive features specifying variable-region sequence identity, selectable functional activity, in vivo depletion threshold, Fc-related structural constraints, FcγR affinity constraints, and in vitro ADCC performance.
Human cd19-binding antibody with defined vh and vl sequences
An isolated purified chimeric, humanized or human monoclonal antibody or fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO.:106 and a VL comprising the amino acid sequence of SEQ ID NO.:111, wherein said antibody binds a human CD19 antigen.
Selectable functional activity for ADCC, apoptosis, proliferation inhibition and in vivo depletion
The antibody possesses a functional activity selected from enhanced ADCC activity, induction of B cell apoptosis, inhibition of B cell proliferation, and in vivo B cell depletion.
In vivo b-cell depletion with a specified threshold
The antibody is capable of depleting selected B-cell types in an animal model, reducing B-cell levels by at least 50% seven days after administration of a 2.5 mg/kg dose.
Fc region complex n-glycoside-linked sugar chain feature
The antibody has 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.
Fc variant affinity constraints for fcγrIIIA and fcγriib
The Fc variant has an affinity for FcγRIIIA that is at least about 5 fold lower than that of a comparable molecule, and an affinity for FcγRIIB within about 2 fold of that of a comparable molecule.
In vitro adcc performance across specific cell lines
The antibody efficiently mediates in vitro ADCC activity against Karpas-422, Karpas-1106P, and DB cell lines but not against Granta-519 cell line.
Claim coverage centers on an isolated purified anti-human CD19 chimeric, humanized or human monoclonal antibody with VH and VL sequences of SEQ ID NO.:106 and SEQ ID NO.:111, and is expanded by dependent claims that specify selectable functional activities, an Fc glycosylation structural feature, FcγR affinity constraints, in vitro ADCC behavior on specified cell lines, and a quantified in vivo B-cell depletion threshold.
Stated Advantages
Mediates immune effector functions including ADCC, CDC and/or apoptosis.
Inhibits anti-IgM/CpG-stimulated B-cell proliferation.
Provides B-cell depletion in an animal model with a specified reduction threshold.
Allows Fc region tuning through complex N-glycoside-linked sugar chain features and Fc variant affinities for FcγRIIIA and FcγRIIB.
Documented Applications
Therapeutic and preventive use across B-cell malignancies, autoimmune diseases, and transplant settings including GVHD, humoral rejection, and post-transplantation lymphoproliferative disorder.
Diagnosis and monitoring using anti-CD19 conjugates, including CD19 density determination and in vivo imaging using PET or SPECT with radiolabeled anti-CD19, including Indium-labeled anti-CD19.
Therapeutic protocols for B cell malignancies using anti-CD19 immunotherapy, including combination regimens with chemotherapeutic agents, radioisotopes, toxins, and other antibodies.
Tumor xenograft efficacy under an anti-CD19 regimen using SCID/Raji lymphoma.
In vivo depletion of immature and mature bone marrow B-cell subsets and IgM+ peritoneal cavity B cells in hCD19tg+/- mice after administration of anti-CD19 antibodies, with % depletion reporting.
Downstream effects on humoral immunity, including immunoglobulin levels and both T cell-independent and T cell-dependent responses, with discussion of autoimmunity.
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