Antibodies to granulocyte-macrophage colony-stimulating factor
Inventors
Bebbington, Christopher R. • Luehrsen, Kenneth • Yarranton, Geoffrey
Assignees
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Publication Number
US-9017674-B2
Publication Date
2015-04-28
Expiration Date
Abstract
The current invention relates to high-affinity antibodies to Granulocyte-Macrophage Colony-Stimulating Factor 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-GM-CSF humanized/humaneered antibodies that reduce immunogenicity and antagonize GM-CSF receptor signaling. The antibodies are defined by specific heavy and light chain variable region determinants, including VH and VL sequences and binding specificity determinants within CDR1, CDR2, and CDR3.
The disclosed CDR sequences include CDR1 NYYIH (SEQ ID NO:25), CDR2 WINAGNGNTKYSQKFQG (SEQ ID NO:27), and CDR3 RQRFPYYFDY (SEQ ID NO:16) for the VH, and CDR1 RASQSVGTNVA (SEQ ID NO:31), CDR2 STSSRAT (SEQ ID NO:33), and CDR3 QQFNKSPLT for the VL. The disclosed antibodies use VH/VL germline-proximal sequences, including human germline VH1/JH4 for the heavy chain and a kappa JK4 sequence for the light chain.
The antibodies are characterized by binding and kinetic targets, including equilibrium dissociation constant (KD) values in the pM range and slow dissociation behavior using surface plasmon resonance/BIACORE-type assessment and dissociation rate constant (kd). The document reports comparable binding to glycosylated and non-glycosylated GM-CSF, competition ELISA demonstrating a shared epitope with a reference chimeric antibody (c19/2-derived Ab2), and improved neutralization potency in a GM-CSF-induced IL-8 U937 assay, reported as lower IC50 compared to the reference.
Claims Coverage
The independent claims define isolated anti-GM-CSF antibodies by specific variable-region CDR sequences and by specific overall variable/constant region sequence identities, covering 2 independent inventive claim sets.
CDR-defined isolated anti-GM-CSF antibody with specified VH and VL sequences
An isolated anti-GM-CSF antibody comprising a VH with CDR1 NYYIH (SEQ ID NO:25), CDR2 WINAGNGNTKYSQKFQG (SEQ ID NO:27), and CDR3 RQRFPYYFDY (SEQ ID NO:16), and a VL with CDR1 RASQSVGTNVA (SEQ ID NO:31), CDR2 STSSRAT (SEQ ID NO:33), and CDR3 QQFNKSPLT.
Sequence-defined isolated anti-GM-CSF antibody with specified VH#, VK# and constant regions
An isolated anti-GM-CSF antibody comprising a VH having a sequence of VH#5 (SEQ ID NO:5), a VL region having a sequence of VK#2 (SEQ ID NO:7), a heavy chain constant region with the amino acid sequence set forth in SEQ ID NO:11, and a kappa light chain constant region with the amino acid sequence set forth in SEQ ID NO:10.
The claim coverage focuses on isolated anti-GM-CSF antibodies defined either by explicit VH/VL CDR amino-acid sequences or by explicit VH#, VK# and constant region sequence identities, with dependent claims adding a pharmaceutical composition including the antibody and a physiologically acceptable carrier.
Stated Advantages
Reduces immunogenicity.
Antagonizes GM-CSF receptor signaling.
Exhibits high-affinity binding to GM-CSF, including pM KD and slow dissociation.
Provides comparable binding to glycosylated and non-glycosylated GM-CSF.
Shares epitope behavior with a reference chimeric antibody (c19/2-derived Ab2) in competition ELISA.
Improves neutralization potency in a GM-CSF-induced IL-8 U937 assay, reflected by a lower IC50.
Documented Applications
Therapeutic treatment areas where GM-CSF is a target, including rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, COPD, diabetes, osteopenia/osteoporosis, Alzheimer’s, and heart failure.
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