FGF21 mimetic antibodies and uses thereof
Inventors
CEBE, Regis • Olland, Stephane • Yowe, David Langdon
Assignees
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Publication Number
US-11692046-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The present disclosure relates to monoclonal antibodies and antigen-binding fragments thereof that bind to human β-klotho, and pharmaceutical compositions and methods of treatment comprising the same.
Core Innovation
The invention relates to isolated β-klotho-binding antibodies or antigen-binding fragments and FGF21 mimetic monoclonal antibodies and antigen-binding fragments that specifically bind human and cynomolgus β-klotho. The antibodies comprise an Fc-independent antigen-binding portion defined by heavy-chain variable region and light-chain variable region sequences, including VH and VL segments with defined CDR combinations and SEQ ID-defined HCDRs and LCDRs.
The disclosed antibodies activate the FGF21 receptor complex FGFR1c–β-klotho to trigger FGF21-mediated signaling and show measured functional properties, including increased phospho-ERK (pERK) activity, binding affinities measured by Biacore, and binding parameters described in terms of Biacore/SET and pERK assays. The document also defines β-klotho binding and epitope mapping, including epitope residues, hydrogen-deuterium exchange (HDx) protection regions, residue ranges, and epitope-defined β-klotho binding characterized by residue regions.
The disclosed antibodies are characterized by competitive binding behavior, including competition with reference antibodies and epitope overlap, and include IgG and Fab formats as well as homologous or conservative antibody variants with maintained functional properties. The document additionally provides nucleic acids coding for the β-klotho-binding antibody or antigen-binding fragment, along with vectors and host cells for expression and downstream isolation and/or purification concepts.
Claims Coverage
The claim coverage centers on one independent claim directed to a nucleic acid coding for a β-klotho-binding antibody or antigen-binding fragment, with inventive sequence-level requirements for both the heavy-chain variable region and the light-chain variable region. The coverage includes dependent refinements that further restrict the SEQ ID NOs and add vector, host-cell, and production embodiments.
Nucleic acid coding a β-klotho-binding antibody with specified heavy- and light-chain variable region sequences
A nucleic acid coding for an antibody or antigen-binding fragment thereof that binds β-klotho, comprising the nucleotide sequences encoding the heavy chain variable region as set forth in SEQ ID NOs: 16, 36, or 38; and the light chain variable region as set forth in SEQ ID Nos: 54, 27, 33, or 40.
Vector comprising the nucleic acid
A vector that includes the nucleic acid comprising the heavy-chain and light-chain variable region nucleotide sequences as specified.
Host cell comprising the vector
A host cell that includes the vector comprising the nucleic acid.
Method of making the β-klotho-binding antibody by host-cell expression and isolation/purification
A method for making an antibody or antigen-binding fragment that binds β-klotho by culturing a host cell to express an assembleable heavy-chain variable region and light-chain variable region, then isolating and/or purifying the antibody or fragment from the culture medium.
Overall, the claim set is anchored in nucleic-acid sequence selection for β-klotho binding, with coverage extending to vectors and host cells containing the nucleic acid, and a production concept involving host-cell culturing followed by isolation and/or purification of the expressed antibody or antigen-binding fragment.
Stated Advantages
Activates the FGF21 receptor complex (FGFR1c–β-klotho) with increased phospho-ERK (pERK) functional activity.
Demonstrates defined β-klotho binding characterized by epitope-binding behavior, HDx protection regions, and epitope mapping.
Shows competitive binding and epitope overlap behavior with reference antibodies.
Differentiates from non-target FGFR isoform complexes by not activating FGFR2c/FGFR3c/FGFR4–β-klotho.
Homologous or conservatively modified antibody variants retain functional properties.
Documented Applications
Formation and use of isolated β-klotho-binding antibodies or antigen-binding fragments that activate the FGF21 receptor complex FGFR1c–β-klotho, characterized by pERK activity and β-klotho epitope binding and competition.
Nucleic-acid and expression embodiments for producing the β-klotho-binding antibody or antigen-binding fragment via a host cell, with downstream isolation and/or purification from culture medium.
Metabolic and cardiovascular disorder treatment is documented, including obesity, type 1/2 diabetes, dyslipidemia, NASH, insulin resistance, and cardiovascular disorders such as atherosclerosis, stroke, and heart failure.
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