Antibodies to EphA3
Inventors
Luehrsen, Kenneth • Martinez, David • Yi, Christina • Bebbington, Christopher R. • Yarranton, Geoffrey T.
Assignees
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Publication Number
US-9290571-B2
Publication Date
2016-03-22
Expiration Date
Abstract
The current invention relates to high-affinity antibodies to EphA3 that have reduced immunogenicity when administered to a human to treat diseases and method of using such antibodies.
Core Innovation
The invention relates to high-affinity anti-EphA3 antibodies with reduced immunogenicity for treating EphA3-dependent diseases. The disclosure frames antibody binding to EphA3 as the basis for therapeutic effect in EphA3-dependent disease settings.
The antibodies are defined by specific engineered variable-region architectures comprising a VH region and a VL region. The VH region includes CDR1, CDR2, and CDR3 with defined amino acid sequences, and the VL region includes CDR1, CDR2, and CDR3 with defined amino acid sequences. The disclosure further specifies framework/region and proviso-style constraints, including human-germline identity constraints and related sequence rules, to achieve reduced immunogenicity.
The disclosure describes antibody formats and effector-configuration options, including IgG with selectable isotypes such as IgG1, IgG2, IgG3, and IgG4, Fab, (Fab')2, and scFv, and mentions options such as active Fc and afucosylated, hypofucosylated, or PEGylated configurations. The functional properties stated include EphA3-specific binding without binding to EphA1, EphA2, EphA5, EphB4, or EphB6 as described, EphA3 activation, induction of apoptosis in EphA3+ leukemia cells, and enhancement of NK-cell ADCC, particularly with afucosylated antibody versus fucosylated antibody.
Claims Coverage
The independent claim covers treatment of a patient with a myeloproliferative disorder whose cells express EphA3 by administering a therapeutically effective amount of an anti-EphA3 antibody defined by specific VH and VL CDR amino acid sequences. The dependent claims further refine the antibody specification and narrow the treated disorder subtype, with inventive features mainly tied to antibody structural definition and selected glycosylation, isotype, and disease subcategory.
CDR-defined anti-EphA3 antibody for EphA3-expressing myeloproliferative disorders
Administering an anti-EphA3 antibody in a therapeutically effective amount to a patient having a myeloproliferative disorder in which the myeloproliferative disorder cells express EphA3, wherein the antibody comprises a VH region having CDR1 with amino acid sequence GYWMN (SEQ ID NO:48), CDR2 with amino acid sequence DIYPGSGNTNYDEKFQG (SEQ ID NO:49), and CDR3 with amino acid sequence GGYYEDFDS (SEQ ID NO:43), and a VL region having CDR1 with amino acid sequence RASQGIISYLA (SEQ ID NO:66), CDR2 with amino acid sequence AASSLQS (SEQ ID NO:68), and CDR3 with sequence GQYANYPYT (SEQ ID NO:57).
The claim coverage centers on using an anti-EphA3 antibody defined by specified VH and VL CDR amino acid sequences for treating an EphA3-expressing myeloproliferative disorder, with dependent refinements directed to isotype and constant-region specifics, afucosylation, and narrowing the treated disorder to idiopathic myelofibrosis or myelodysplastic syndrome as reflected in the related dependent claim set provided.
Stated Advantages
High affinity EphA3 binding is stated, including low-nanomolar affinity and often pM in examples.
Reduced immunogenicity is stated for the engineered antibodies.
EphA3 activation is stated.
EphA3-specific binding without binding to EphA1, EphA2, EphA5, EphB4, or EphB6 is stated.
Apoptosis induction in EphA3+ leukemia cells is stated, including comparison between Fab and (Fab')2.
Enhanced NK-cell ADCC is stated for afucosylated antibody versus fucosylated antibody.
Documented Applications
Treating a patient with a myeloproliferative disorder in which the myeloproliferative disorder cells express EphA3.
Treating idiopathic myelofibrosis.
Treating myelodysplastic syndrome.
Treating solid tumors with EphA3 expression.
Treating acute myeloid leukemia (AML) and chronic myeloid leukemia (CML).
Treating polycythemia vera and essential thrombocythemia.
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